A Two-Step Procedure for the Overall Transamidation of 8-Aminoquinoline Amides Proceeding via the Intermediate N -Acyl-Boc-Carbamates

Article abstract of DOI:10.1021/acs.joc.8b00174

Herein a two-step strategy for achieving overall transamidation of 8-aminoquinoline amides has been explored. In this protocol, the 8-aminoquinoline amides were first treated with Boc₂O and DMAP to form the corresponding N-acyl-Boc-carbamates,

Full text of DOI:10.1021/acs.joc.8b00174

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A Two-step Procedure for the Overall Transamidation of 8-Aminoquinoline
Amides Proceeding via the Intermediate N-Acyl-Boc-Carbamates
Oscar Verho, Monireh Pourghasemi Lati, and Michael Oschmann
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00174 • Publication Date (Web): 26 Mar 2018
Downloaded from http://pubs.acs.org on March 26, 2018
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A Two-step Procedure for the Overall Transamidation of 8-Aminoquinoline Amides
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Proceeding via the Intermediate N-Acyl-Boc-Carbamates
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Oscar Verho,* Monireh Pourghasemi Lati, Michael Oschmann,
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Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SEꢀ106 91
Stockholm, Sweden.
ABSTRACT GRAPHICS
ABSTRACT
Herein, a twoꢀstep strategy for achieving overall transamidation of 8ꢀaminoquinoline amides has
been explored. In this protocol, the 8ꢀaminoquinoline amides were first treated with Boc2O and
DMAP to form the corresponding NꢀacylꢀBocꢀcarbamates, which were found to be sufficiently
reactive to undergo subsequent aminolysis with different amines in the absence of any additional
reagents or catalysts. To demonstrate the utility of this approach, it was applied on a number of
8ꢀaminoquinoline amides from the recent C–H functionalization literature, enabling access to a
range of elaborate amide derivatives in good to high yields.
INTRODUCTION
The combination of transitionꢀmetal catalysis and bidentate directing groups has recently
emerged as a powerful and broadly applicable strategy for achieving the functionalization of
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unactivated C–H bonds.1 A particularly appealing feature of this approach from a synthetic
chemistry point of view is that it allows for rapid buildꢀup of molecular complexity while
offering high control of regioꢀ and stereochemistry. Among the assorted bidentate directing
groups available today, 8ꢀaminoquinoline (8ꢀAQ) introduced by Daugulis and coꢀworkers in
2005,2 constitutes one of the most successful auxiliaries for carrying out the activation and
functionalization of C(sp2)–H and C(sp3)–H bonds.1a,1b,3 Taking the functionalization of aromatic
C(sp2)–H bonds as one illustrative example, one can find a variety of catalytic protocols
employing different transition metals and the 8ꢀAQ directing group for the formation of new
carbonꢀcarbon2,4 and carbonꢀheteroatom bonds.5 However, it is important to point out that 8ꢀAQꢀ
directed C–H functionalization has also been successfully used for other, more challenging,
classes of substrates.1 As a result, this synthetic approach has found extensive use in the
preparations of natural products and other drugꢀlike compounds,6 where it often allows for
precise control of the stereochemistry and stepꢀefficient syntheses.
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For synthetic strategies that rely on directed C–H functionalization to be practical, the
auxiliary must be readily removed when it is no longer needed. In pursuit of this goal, a number
of methods have been reported for the cleavage of the 8ꢀAQ directing group (Figure 1). The most
straightforward approach to cleave the 8ꢀAQ auxiliary is to carry out a direct hydrolysis at high
temperatures to afford the free carboxylic acid under either strongly acidic4h,5b,6d or strongly basic
conditions.5j,6a Unfortunately, this approach requires that the substrate is robust and does not
contain any other acidꢀ or baseꢀlabile functional groups, otherwise the yield of the desired acid
product will be low. Another commonly used strategy that enables milder hydrolysis conditions
involves activation of the 8ꢀAQ amides by either Nꢀmethylation4g,5g,6e,7 or Bocꢀprotection.6a,6b,6d,8
Maulide and coꢀworkers have also shown that the 8ꢀAQ directing group can be activated through
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an ozonolysis/reductive quenchingꢀsequence to form a labile imide intermediate that can
subsequently be converted to either the corresponding carboxylic acid or primary amide
depending on whether LiOH/H2O2 or NH4OH is used.9
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R2 = H, NH2, OH, OR
Previous approaches
reduction
ozono- & aminolysis
hydrolysis
O
O
O
R1
R1
H
R2
N
N
esterification
C-H
functionalization
(R1-X)
H
H
N
N
O
8-AQ amides
C–H functionalized
products with the
8-AQ auxiliary
N-Boc activation
then R3NHR4
R1
R3
N
R4
This work
Figure 1. Approaches for the transformation of C–H functionalized products with the 8ꢀAQ
auxiliary into different classes of compounds.
Different ways to transform 8ꢀAQ amides include reduction to the corresponding
aldehydes4g,6e,6f,10 and various esterification protocols that provide the corresponding esters.4k,11
However, to the best of our knowledge, there is no prior study that has thoroughly evaluated the
potential of 8ꢀAQ amides to undergo transamidation. After surveying the literature on
transamidation chemistry,12 we were particularly inspired by a recent metalꢀfree protocol
developed by the Szostak group13 and were keen to investigate if it was also feasible to
transamidate 8ꢀAQ amides in a similar fashion. This metalꢀfree approach to achieve overall
transamidation relies on destabilization of the amide bond through the generation of an
intermediate NꢀacylꢀBocꢀcarbamate with a highly twisted amide bond with diminished capability
for amidic resonance (cf. the resonance energy of NꢀBocꢀbenzanilide on 7.2 kcal/mol to that of
acetamide of 19.1 kcal/mol).13,14 In the context of this proposed strategy to transamidate 8ꢀAQ
amides, it is also worth highlighting a recent Znꢀcatalyzed protocol reported by the group of
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Maes to transform amides carrying a related nicotinate auxiliary into different ester or amide
derivatives.15
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RESULTS AND DISCUSSION
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Preliminary trials were performed on the simple Bocꢀprotected model substrate 2a using
piperonylamine as the amine nucleophile with the initial aim of studying the overall feasibility of
this methodology (see Supporting Information (SI), Figures S1 and S2). In accordance with the
NꢀacylꢀBocꢀcarbamates studied by the Szostak group,13 model substrate 2a was found to be
readily converted to amide product 3a even at ambient temperature without any added catalyst.16
However, the aminolysis of 2a was found to be most efficient at 60 °C and when it was
performed with 1.5 equiv piperonylamine in toluene (0.5 M) product 3a could be isolated in 98%
yield after 7 h.
After establishing that the transamidation of 8ꢀAQ amides was indeed a feasible
transformation, we wanted to evaluate the efficiency of this reaction on more elaborate substrates
selected from the recent C–H functionalization literature.17 We envisioned that such a
transamidation strategy would provide rapid access to a diverse set of amide derivatives if it
were to be used in conjunction with various C–H functionalization methods or other 8ꢀAQ
directed transformations. To demonstrate this concept, NꢀBoc protection of the selected
substrates was first carried out (typically done in 74ꢀ98% yield using Boc2O/DMAP in MeCN
for 1ꢀ2 h at 60 °C, see experimental section for details). The obtained NꢀacylꢀBocꢀcarbamates
were then subjected to piperonylamine in toluene at 60 °C (Scheme 1). Attempts to extend the
transamidation methodology to orthoꢀsubstituted 8ꢀAQ benzamides, such as carbamates 2b and
2c, worked poorly as the aminolysis step furnished low yields of the desired products 3b and 3c.
These results suggest that an increased steric bulk around the Bocꢀamide moiety was detrimental
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to the aminolysis reaction. Instead, the major product from these reactions were the NꢀBocꢀ
deprotected compounds 1b and 1c, resulting from the transfer of the Boc group to
piperonylamine.18
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To our delight, the protocol was found to be significantly more effective when extended to
several other classes of 8ꢀAQ amides. For example, a variety of aliphatic 8ꢀAQ amides could
efficiently be transamidated by this twoꢀstep approach. Carbamates 2d and 2e, which are
accessible via synthetic routes involving directed βꢀarylation of linear aliphatic 8ꢀAQ amides
(precursors D and E, Table S1), were converted to the corresponding amides 3d and 3e in 81%
and 84% yield, respectively. The presence of a TIPSꢀprotected alkyne moiety in the substrate was
also wellꢀtolerated, as demonstrated by the reaction of carbamate 2f to provide product 3f in 91%
yield after 8 h. Carbamate 2g was included in our substrate scope investigation as a surrogate for
more elaborate linear 8ꢀAQ amides carrying substituents in the αꢀposition, and it was found to
undergo significant aminolysis after 8 h, allowing product 3g to be isolated in 71% yield.
Carbamates 2h and 2i, obtained through synthetic routes involving directed alkene
hydroamination of a homoallylic 8ꢀAQ amide (precursor G, Table S1) with either phthalimide or
ethyl 2ꢀnitropropionate, could be converted into products 3h and 3i in 73% and 88% yield,
respectively, after 9 h. Here, product 3i obtained in 88% yield is worth particular mentioning as it
demonstrates that this transamidation chemistry can be carried out selectively in the presence of
an ester group. In contrast, chemoselective cleavage of the 8ꢀAQ auxiliary from 3i through
hydrolysis would be challenging as the ester group would also be prone to hydrolyze under such
reaction conditions.
The same homoallylic 8ꢀAQ amide (precursor G) could also be used to access carbamate 2h
through Pdꢀcatalyzed β,γꢀvicinal dicarbofunctionalization followed by Boc protection, which in
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turn was transformed into product 3h in 78% yield after 24 h. Noteworthily, all the reactions
involving the less hindered aliphatic carbamates 2dꢀj were found to produce low amounts of the
Boc deprotected byproducts 1dꢀj, which further supported the hypothesis that significant steric
bulk around the NꢀBoc amide moiety favors this undesired reaction path.
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Scheme 1. Scope of the transamidation strategy in terms of different 8ꢀaminoquinoline amides.a
aReaction conditions unless otherwise noted: NꢀBoc protection step: Substrate 1aꢀp (1 equiv),
Boc2O (2 equiv) and DMAP (0.1 equiv) in MeCN (0.1 M), 60 °C, 1ꢀ2 h. Aminolysis step:
Carbamate 2aꢀp (1 equiv), piperonylamine (1.5 equiv), toluene (0.5 M), 60 °C. All yields refer to
isolated yields following column chromatography (from 2aꢀp to 3aꢀp) unless otherwise stated.
1
bProduct 3b was not isolated, instead the yield was estimated by HꢀNMR from the ratio of 1b,
c
d
2b and 3b. 3e was isolated after precipitation from the reaction mixture. Reaction was
performed in DMF (0.5 M).e2 equiv of piperonylamine were used.
Interestingly, also furan carbamates 2kꢀm prepared via directed C3ꢀarylation chemistry could
be efficiently converted to products 3kꢀm in high yields. Here, the successful aminolysis of
carbamate 2m further demonstrates the compatibility of the present transamidation protocol
towards esterꢀcontaining substrates, and highlights that it also can be applied to substrates
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containing benzoate ester moieties. For the C3ꢀalkylated thiophene carbamates 2n and 2o the
transamidation was found to be slower, requiring 2 equiv of piperonylamine and extended
reaction times to furnish satisfactory yields of products 3n and 3o. For these two reactions, Boc
deprotection was found to occur to a greater extent and the side products 1n and 1o were
obtained in ca 15% yield from each reaction. Also cyclopropaneꢀtype substrates were applicable
for this method, as exemplified by the transformation of 2p to 3p, which was carried out in 76%
yield when performed with 2 equiv of piperonylamine in DMF for 24 h.
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After having surveyed a series of NꢀacylꢀBoc carbamates, we then focused on investigating
the efficiency of the aminolysis step with different amine nucleophiles, using carbamates 2e and
2k as the model substrates (Scheme 2). Benzylamine and 4ꢀ(trifluoromethyl)benzylamine reacted
slower with furan carbamate 2k than piperonylamine; however, by extending the reaction times
both products 4a and 4b could be obtained in high yields (81% and 84%, respectively). The
presence of a free phenol moiety did not have any significant negative effect on the reaction
outcome and product 4c was acquired in 76% yield when the aminolysis was performed in DMF
for 9 h. Both 2ꢀpicolylamine and tryptamine proved to be competent nucleophiles for the
reaction with substrate 2k as well, and the corresponding amides 4d and 4e were acquired in
82% and 81% yield, respectively. Propargylamine could also be used for the aminolysis, but the
high volatility of this reagent led to a less efficient reaction with carbamate 2k. However,
performing this reaction with 3 equiv of propargylamine for 24 h allowed amide 4f to be isolated
in 86% yield.
For other less volatile linear aliphatic primary amines, such as hexylamine or 3ꢀ
methoxypropylamine, 1.5 equiv proved sufficient in the reactions with carbamate 2e, giving
products 4g and 4h in 72% and 73% yield, respectively, after shorter reaction times. More
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hindered amines were found to produce substantial amounts of the Bocꢀdeprotected byproduct,
which reduced the yields of the desired amide products. The reactions between carbamate 2e and
the amines cyclohexylamine and (R)ꢀ1ꢀphenylethylamine gave only 64% and 52% yield of
products 4i and 4j, respectively, despite the reactions being pushed to >95% conversion with
increased amine stoichiometry and extended reaction times. A similar outcome was also
observed for the reaction between the secondary amine Nꢀmethylbenzylamine (5 equiv) and
carbamate 2e, where product 4k was obtained in a low yield of 32% after 30 h and where the
Bocꢀdeprotected side product 1e almost exclusively accounted for the remaining mass balance.
Pyrrolidine was found to react more efficiently with carbamate 2e and full conversion was
reached already after 8 h, but also for this reaction the selectivity was low and product 4l was
isolated in merely 54% yield. Dimethylamine solution (2 M in THF, 10 equiv) could also be used
to trigger aminolysis of carbamate 2e, but in line with the other entries involving sterically
encumbered amines nucleophiles the outcome of the reaction was disappointing as only 34%
yield of product 4m was obtained after 7 h.
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Scheme 2. Aminolysis of 2e and 2i with different amine nucleophiles.a
aReaction conditions unless otherwise noted: 8ꢀaminoquinoline amide substrate (1 equiv), amine
(1.5ꢀ5.0 equiv), toluene (0.5 M), 60 °C. All yields refer to isolated yields following column
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b
chromatography. Reaction was performed in DMF (0.5 M).cReaction was performed with 0.4
mmol 2e in dimethylamine solution (2 M in THF, 2 mL).
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Interestingly, successful aminolysis could be achieved with an anilineꢀtype nucleophile,
which was beyond the scope of the earlier metalꢀfree method reported by Szostak and coꢀ
workers.13 However, this reaction was slow due to the low nucleophilicity of pꢀanisidine,
requiring additional alterations of the reaction conditions. As shown in Scheme 3, when the
aminolysis was performed at 80 °C for 48 h with 5 equiv of pꢀanisidine, product 4n was obtained
in 52% yield. Noteworthily, this reaction appeared to be very selective towards the formation of
4n, as unreacted starting material accounted for most of the remaining material, and only trace
amounts of the Bocꢀdeprotected byproduct 1e were observed from 1HꢀNMR analysis of the crude
reaction mixture. However, it is important to emphasize that previous transamidation protocols
based on Pdꢀ,12a,12c Niꢀ,12b,12d,12e Cuꢀ,12g and Znꢀcatalysis15 constitute more efficient and more
general options for carrying out transamidations with aniline nucleophiles.
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Scheme 3. Aminolysis with an aniline.
It is also important to highlight that for all entries shown in Schemes 1 and 2, the NꢀacylꢀBoc
carbamates had all been purified by column chromatography prior to the aminolysis step.
However, as demonstrated by the overall transamidation of 1d, it is also possible to perform both
steps in oneꢀpot (Scheme 4). With this oneꢀpot procedure, amide 3d was obtained in 53% yield
after a single column chromatography purification.19
Scheme 4. Oneꢀpot protocol for overall transamidation.
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CONCLUSION
In summary, the aminolysis of NꢀacylꢀBocꢀcarbamates prepared from different 8ꢀ
aminoquinoline amides has been evaluated, as this was identified as a convenient approach to
achieve overall transamidation of these synthetically useful amide compounds. In many cases,
the carbamates were found to undergo facile aminolysis under mild conditions to give a variety
of amide products in good to high yields, without the need for any additional additives.
Additional advantages of this method are that it tolerates substrates containing hydrolysisꢀ
sensitive functional groups as well as an aniline as the nucleophile, and moreover it can be
modified to work in a oneꢀpot fashion. However, the method also has limitations, as exemplified
by the aminolysis reactions involving stericallyꢀhindered substrates, which gave lower yields of
the desired amide products, despite the use of more forcing reaction conditions. Overall, the
method offers a useful and alternative way to transform 8ꢀaminoquinoline amides into other
more elaborate amide derivatives, and circumvents the need of proceeding via the intermediate
carboxylic acid that is associated with the subsequent use of coupling reagents to form the
desired amide bond.
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EXPERIMENTAL SECTION
General Experimental Information
All reagents and solvents were purchased and used as received from commercial vendors or
synthesized according to cited procedures. 8ꢀAminoquinoline amides 1aꢀp were obtained using
previously reported procedures (see Table S1 in the SI for further details). Oxygen and/or
moisture sensitive reactions were carried out in oven or flameꢀdried glassware under nitrogen
atmosphere using appropriately dried solvents. Yields refer to chromatographically isolated
compounds, unless otherwise stated. Room temperature in laboratory (21ꢀ23 °C). Trace
impurities of CH2Cl2 in some spectra originates from the process of transferring compounds
between containers, where this solvent was used for washing. Flash chromatography was
performed using 15ꢀ45 µm silica gel cartridges (60Å mesh) on a Teledyne Isco Combiflash Rf.
SiliaSep SiO2 cartridges used for these purifications were provided from SiliCycle. Analytical
thin layer chromatography (TLC) was performed on 0.25 mm silica gel 60ꢀF plates and
visualized by UV light (254 nm) or suitable TLC stain. Chemical shifts are reported in parts per
million (ppm) relative to the NMR solvent peaks. Nuclear Magnetic Resonance Spectroscopy
(NMR) were recorded on a Bruker Advance spectrometer (1H, 13C and FꢀNMR). Deuterated
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solvents for NMR analyses was obtained from SigmaꢀAldrich. Data for HꢀNMR are reported as
follows: chemical shift, multiplicity (br = broad, s = singlet, d = doublet, t = triplet, m =
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multiplet), coupling constants, and integration. High resolution mass spectroscopy (HRMS) was
performed on Bruker microTOF/ESI mass spectrometer. Infrared spectra were obtained with a
“Spectrum One” instrument from PerkinꢀElmer or a Nicolet iS5 instrument with fullꢀdiamond
crystal ATR from ThermoꢀFisher.
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General Procedure A for the N-Boc protection of substrates 1a-p
This general procedure was used for all NꢀBoc protection reactions unless otherwise stated. To a
reaction vessel containing 8ꢀaminoquinoline amide substrate 1aꢀp (1 equiv) and 4ꢀ
(dimethylamino)pyridine (DMAP, 0.1 equiv) were added Boc anhydride (Boc2O, 2 equiv) in dry
MeCN (0.1 M). The reactions were allowed to stir at 60 °C for 1ꢀ2 h, after which they were
concentrated in vacuo and purified by column chromatography (SiO2) to give the corresponding
carbamates 2aꢀp.
General Procedure B for the aminolysis of substrates 2a-p
This general procedure was used for all aminolysis reactions described in Scheme 1 and Scheme
2, unless otherwise stated. To a sealed vial containing the Bocꢀprotected substrates 2aꢀp (0.20
mmol, 1 equiv), was added the amine (0.30ꢀ1.00 mmol, 1.5ꢀ5.0 equiv) in toluene or DMF, and
the reaction was allowed to stir at 60 °C for 7ꢀ30 h. The reactions were then concentrated in
vacuo and purified by column chromatography (SiO2) to give products 3aꢀp and 4aꢀl.
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Tertꢀbutyl benzoyl(quinolinꢀ8ꢀyl)carbamate (2a): The reaction was performed according to
general procedure A with 4.0 mmol 1a for 1 h. The product was isolated after column
chromatography (gradient 0ꢀ50% EtOAc in pentane) in 1.30 g (93%) as a pale yellow amorphous
solid. 1H-NMR (400 MHz, CDCl3, 298 K) δ 8.89 (dd, J = 4.2, 1.7 Hz, 1H), 8.17 (dd, J = 8.3, 1.7
Hz, 1H), 7.96–7.94 (m, 2H), 7.83 (dd, J = 8.2, 1.3 Hz, 1H), 7.69 (dd, J = 7.4, 1.4 Hz, 1H), 7.60–
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7.51 (m, 2H), 7.47–7.39 (m, 3H), 1.21 (s, 9H). C-NMR (100 MHz, CDCl3, 298 K) δ 173.5,
153.5, 150.5, 144.1, 137.5, 137.3, 136.1, 131.3, 129.2, 129.1, 128.6, 128.2, 128.0, 126.2, 121.7,
83.1, 27.5. IR (thin film) νmax 2980, 1737, 1683, 1369, 1349, 1275, 1260, 1153, 764. HRMS
(ESI-TOF) m/z: [M + Na]+ Calcd for C21H20N2O3Na 371.1372; Found 371.1366.
Tertꢀbutyl (2ꢀmethylbenzoyl)(quinolinꢀ8ꢀyl)carbamate (2b). The reaction was performed
according to general procedure A with 0.8 mmol 1b for 1 h. The product was isolated after
column chromatography (gradient 0ꢀ50% EtOAc in pentane) in 265 mg (91%) as a yellow
amorphous solid. 1H-NMR (400 MHz, CDCl3, 298 K) δ 8.91 (dd, J = 4.2, 1.7 Hz, 1H), 8.18 (dd,
J = 8.4, 1.7 Hz, 1H), 7.92–7.90 (m, 1H), 7.85 (dd, J = 8.2, 1.4 Hz, 1H), 7.72 (dd, J = 7.3, 1.4 Hz,
1H), 7.60 (dd, J = 8.2, 7.3 Hz, 1H), 7.42 (dd, J = 8.4, 4.2 Hz, 1H), 7.36–7.33 (m, 1H), 7.28–7.25
(m, 2H + CHCl3), 2.56 (s, 3H), 1.15 (s, 9H). 13C-NMR (100 MHz, CDCl3, 298 K) δ 173.2,
153.1, 150.4, 144.2, 138.2, 136.7, 136.1, 136.0, 130.5, 129.7, 129.20, 129.18, 128.4, 127.3,
126.2, 125.3, 121.6, 83.1, 27.3, 19.6. IR (thin film) νmax 2985, 1736, 1683, 1349, 1275, 1261,
764. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C22H22N2O3Na 385.1528; Found 385.1522.
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Tertꢀbutyl ([1,1'ꢀbiphenyl]ꢀ2ꢀcarbonyl)(quinolinꢀ8ꢀyl)carbamate (2c). The reaction was
performed according to general procedure A with 0.8 mmol 1c for 1 h. No column
chromatography purification was performed for 2c, instead the product precipitated directly from
the crude reaction solution and could be obtained in 299 mg (71%) as a colorless amorphous
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solid, after washing with cold MeCN. H-NMR (400 MHz, CDCl3, 298 K) δ 8.90 (dd, J = 4.1,
1.6 Hz, 1H), 8.13 (dd, J = 8.2, 1.4 Hz, 1H), 7.87 (d, J = 7.4 Hz, 1H), 7.79 (dd, J = 8.2, 1.0 Hz,
1H), 7.63 (d, J = 7.4 Hz, 2H), 7.53–7.38 (m, 8H), 7.32–7.30 (m, 1H), 1.11 (s, 9H). 13C-NMR
(100 MHz, CDCl3, 298 K) δ 172.7, 152.4, 150.4, 144.4, 140.4, 139.5, 137.7, 136.4, 135.9, 129.8,
129.6, 129.2, 129.0, 128.8, 128.3, 128.2, 127.7, 127.5, 127.0, 126.1, 121.5, 83.0, 27.5. IR (thin
film) νmax 2987, 1742, 1683, 1368, 1352, 1275, 1261, 1154, 764. HRMS (ESI-TOF) m/z: [M +
Na]+ Calcd for C27H24N2O3Na 447.1685; Found 447.1675.
Tertꢀbutyl (3ꢀ(4ꢀmethoxyphenyl)butanoyl)(quinolinꢀ8ꢀyl)carbamate (2d). The reaction was
performed according to general procedure A with 1.5 mmol 1d for 1 h. The product was isolated
after column chromatography (gradient 0ꢀ50% EtOAc in pentane) in 501 mg (80%) as an orange
foamy solid. 1H-NMR (400 MHz, CDCl3, 298 K) δ 8.86 (dd, J = 4.2, 1.7 Hz, 1H), 8.14 (dd, J =
8.4, 1.7 Hz, 1H), 7.78 (dd, J = 8.4, 1.3 Hz, 1H), 7.49 (dd, J = 8.0, 7.4 Hz, 1H), 7.39 (dd, J = 8.3,
4.2 Hz, 1H), 7.28–7.22 (m, 3H + CHCl3), 6.87–6.83 (m, 2H), 3.80 (s, 3H), 3.49–3.32 (m, 3H),
1.36 (d, J = 6.7 Hz, 3H), 1.21 (s, 9H). 13C-NMR (100 MHz, CDCl3, 298 K) δ 175.2, 157.9,
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153.0, 150.3, 144.2, 138.9, 137.0, 135.9, 128.9, 128.8, 128.0, 127.9, 126.1, 121.4, 113.8, 82.4,
55.3, 46.2, 35.6, 27.6, 22.3. IR (thin film) νmax 2977, 1737, 1702, 1514, 1369, 1275, 1260, 1155,
764. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C25H28N2O4Na 443.1947; Found 443.1938.
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Tertꢀbutyl (3,3ꢀdiphenylpropanoyl)(quinolinꢀ8ꢀyl)carbamate (2e). The reaction was performed
according to general procedure A with 0.4 mmol 1e for 1 h. The product was isolated after
column chromatography (gradient 0ꢀ60% EtOAc in pentane) in 178 mg (97%) as a yellow foamy
solid. 1H-NMR (400 MHz, CDCl3, 298 K) δ 8.85 (dd, J = 4.2, 1.7 Hz, 1H), 8.12 (dd, J = 8.4, 1.7
Hz, 1H), 7.75 (dd, J = 8.4, 1.3 Hz, 1H), 7.44 (dd, J = 8.1, 7.4 Hz, 1H), 7.39–7.28 (m, 9H), 7.20
(tt, J = 7.2, 1.3 Hz, 2H), 7.08 (dd, J = 7.4, 1.3 Hz, 1H), 4.76 (t, J = 7.7 Hz, 1H), 3.98 (d, J = 7.7
Hz, 2H), 1.24 (s, 9H). 13C-NMR (100 MHz, CDCl3, 298 K) δ 174.7, 153.0, 150.3, 144.3, 144.2,
136.9, 135.9, 128.81, 128.79, 128.5, 128.1, 127.9, 126.3, 126.1, 121.4, 82.6, 47.2, 43.8, 27.7. IR
(thin film) νmax 2980, 1736, 1704, 1369, 1275, 1261, 1154, 1123, 764. HRMS (ESI-TOF) m/z:
[M + Na]+ Calcd for C29H28N2O3Na 475.1998; Found 475.1986.
Tertꢀbutyl (3ꢀphenylꢀ5ꢀ(triisopropylsilyl)pentꢀ4ꢀynoyl)(quinolinꢀ8ꢀyl)carbamate (2f). The
reaction was performed according to general procedure A with 0.5 mmol 1f for 1 h. The product
was isolated after column chromatography (gradient 0ꢀ40% EtOAc in pentane) in 237 mg (85%)
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as a yellow gel. 1H-NMR (400 MHz, CDCl3, 298 K) δ 8.85 (dd, J = 4.2, 1.7 Hz, 1H), 8.15 (dd, J
= 8.3, 1.7 Hz, 1H), 7.80 (dd, J = 8.3, 1.4 Hz, 1H), 7.53–7.49 (m, 3H), 7.41–7.36 (m, 2H), 7.35–
7.30 (m, 2H), 7.26–7.22 (m, 1H), 4.45 (t, J = 7.2 Hz, 1H), 3.63 (d, J = 7.2 Hz, 2H), 1.21 (s, 9H),
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1.10–1.07 (m, 21H). C-NMR (100 MHz, CDCl3, 298 K) δ 173.4, 152.8, 150.3, 144.2, 141.2,
136.8, 135.9, 129.0, 128.8, 128.4, 128.1, 127.9, 126.8, 126.1, 121.4, 109.6, 83.1, 82.7, 47.2, 35.1,
27.6, 18.7, 11.3. IR (thin film) νmax 2942, 2865, 1739, 1708, 1296, 1259, 1156, 1124, 764.
HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C34H44N2O3SiNa 579.3019; Found 579.3001.
Tertꢀbutyl (2ꢀphenylbutanoyl)(quinolinꢀ8ꢀyl)carbamate (2g). The reaction was performed
according to general procedure A with 0.8 mmol 1g for 2 h. The product was isolated after
column chromatography (gradient 0ꢀ40% EtOAc in pentane) in 232 mg (74%) as a yellow foamy
solid. 1H-NMR (400 MHz, CDCl3, 298 K) δ 8.86 (dd, J = 4.1, 1.6 Hz, 1H), 8.13 (dd, J = 8.3, 1.6
Hz, 1H), 7.77 (dd, J = 8.3, 1.2 Hz, 1H), 7.47 (dd, J = 8.1, 7.5 Hz, 1H), 7.41–7.30 (m, 5H), 7.29–
7.23 (m, 2H), 4.87 (bs, 1H), 2.29–2.19 (m, 1H), 1.89–1.79 (m, 1H), 1.16 (s, 9H), 0.92 (t, 7.2 Hz).
13C-NMR (100 MHz, CDCl3, 298 K) δ 177.1, 152.7, 150.3, 144.4, 140.0, 137.3, 135.8, 128.80,
128.78, 128.6, 128.3, 127.8, 126.8, 126.0, 121.5, 82.3, 53.1, 27.5, 27.4, 12.1. IR (thin film) νmax
2967, 1733, 1700, 1367, 1289, 1251, 1150, 1122, 789. HRMS (ESI-TOF) m/z: [M + Na]+
Calcd for C24H26N2O3Na 413.1841; Found 413.1847.
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Tertꢀbutyl (4ꢀ(1,3ꢀdioxoisoindolinꢀ2ꢀyl)butanoyl)(quinolinꢀ8ꢀyl)carbamate (2h). The reaction
was performed according to general procedure A with 0.4 mmol 1h for 1 h. The product was
isolated after column chromatography (gradient 0ꢀ60% EtOAc in pentane) in 165 mg (90%) as a
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yellow foamy solid. H-NMR (400 MHz, CDCl3, 298 K) δ 8.86 (dd, J = 4.2, 1.7 Hz, 1H), 8.13
(dd, J = 8.3, 1.7 Hz, 1H), 7.84–7.82 (m, 2H), 7.78 (dd, J = 8.0, 1.7 Hz, 1H), 7.70–7.67 (m, 2H),
7.58–7.51 (m, 2H), 7.37 (dd, J = 8.3, 4.2 Hz, 1H), 3.82 (t, J = 6.9 Hz, 2H), 3.21 (t, J = 7.3 Hz,
2H), 2.16–2.09 (m, 2H), 1.19 (s, 9H). 13C-NMR (100 MHz, CDCl3, 298 K) δ 175.3, 168.5,
152.8, 150.4, 144.1, 136.9, 136.0, 133.8, 132.3, 129.1, 128.9, 128.0, 126.1, 123.2, 121.4, 82.6,
37.4, 35.2, 27.6, 24.1. IR (thin film) νmax 2977, 2932, 1738, 1712, 1396, 1369, 1296, 1272, 1255,
1157, 1125, 721. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C26H25N3O5Na 482.1692; Found
482.1683.
ethyl 6ꢀ((tertꢀbutoxycarbonyl)(quinolinꢀ8ꢀyl)amino)ꢀ2ꢀmethylꢀ2ꢀnitroꢀ6ꢀoxohexanoate (2i) The
reaction was performed according to general procedure A with 0.39 mmol 1i for 2 h. The product
was isolated after column chromatography (gradient 10ꢀ50% EtOAc in pentane) in 159 mg
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(89%) as a yellow oil. H-NMR (400 MHz, CDCl3, 298 K) δ 8.88 (dd, J = 4.2, 1.7 Hz, 1H),
8.16 (dd, J = 8.3, 1.7 Hz, 1H), 7.81 (dd, J = 8.1, 1.6 Hz, 1H), 7.57–7.49 (m, 2H), 7.40 (dd, J =
8.3, 4.2 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 3.22 (t, J = 7.0 Hz, 2H), 2.41–2.26 (m, 2H), 1.85–1.74
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(overlapping m and s, 1H + 3H), 1.72–1.61 (m, 1H), 1.26 (t, J = 7.1 Hz, 3H), 1.22 (s, 9H). C-
NMR (100 MHz, CDCl3, 298 K) δ 175.3, 167.4, 152.9, 150.5, 144.0, 136.8, 136.0, 129.0, 128.9,
128.1, 126.1, 121.5, 92.8, 82.7, 62.7, 37.3, 35.7, 27.6, 21.1, 19.2, 13.8. IR (thin film) νmax 2977,
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for C23H29N3O7Na 482.1903; Found 482.1901.
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Tertꢀbutyl
(3ꢀ(4ꢀchlorophenyl)ꢀ4ꢀ(1ꢀmethylꢀ1Hꢀindolꢀ3ꢀyl)butanoyl)(quinolinꢀ8ꢀyl)carbamate
(2j). The reaction was performed according to general procedure A with 0.4 mmol 1j for 2 h.
The product was isolated after column chromatography (gradient 0ꢀ50% EtOAc in pentane) in
170 mg (76%) as a yellow foamy solid. 1H-NMR (400 MHz, CDCl3, 298 K) δ 8.80 (dd, J = 4.2,
1.7 Hz, 1H), 8.13 (dd, J = 8.3, 1.5 Hz, 1H), 7.78 (dd, J = 8.3, 1.3 Hz, 1H), 7.58 (d, J = 8.0 Hz,
1H), 7.49 (dd, J = 8.1, 7.4 Hz, 1H), 7.37 (dd, J = 8.3, 4.2 Hz, 1H), 7.25–7.16 (m, 7H), 7.06–7.01
(m, 1H), 6.62 (s, 1H), 3.77–3.70 (m, 1H), 3.67 (s, 3H), 3.63–3.52 (m, 2H), 3.25 (dd, J = 14.2, 6.3
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Hz, 1H), 3.03 (dd, J = 14.2, 8.3 Hz, 1H), 1.21 (s, 9H). C-NMR (100 MHz, CD3CN, 298 K) δ
174.6, 152.8, 150.4, 144.0, 143.9, 137.02, 136.98, 136.2, 131.2, 129.6, 128.9, 128.8, 128.1,
128.04, 128.00, 127.6, 126.1, 121.7, 121.2, 118.9, 118.5, 112.0, 109.3, 82.4, 43.8, 42.5, 31.9,
31.8, 26.8. IR (thin film) νmax 2979, 2932, 1736, 1701, 1492, 1474, 1369, 1322, 1296, 1255,
1156, 1124, 742. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C33H32ClN3O3Na 576.2030;
Found 576.2023.
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Tertꢀbutyl (3ꢀ(4ꢀmethoxyphenyl)furanꢀ2ꢀcarbonyl)(quinolinꢀ8ꢀyl)carbamate (2k). The reaction
was performed according to general procedure A with 0.5 mmol 1k for 1 h. The product was
isolated after column chromatography (gradient 10ꢀ75% EtOAc in pentane) in 219 mg (98%) as
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an orange foamy solid. H-NMR (400 MHz, CDCl3, 298 K) δ 8.87 (dd, J = 4.2, 1.7 Hz, 1H),
8.16 (dd, J = 8.3, 1.7 Hz, 1H), 7.80 (dd, J = 8.3, 1.4 Hz, 1H), 7.71–7.67 (m, 2H), 7.64 (dd, J =
7.5, 1.4 Hz, 1H), 7.57–7.53 (m, 2H), 7.39 (dd, J = 8.4, 4.2 Hz, 1H), 6.90–6.87 (m, 2H), 6.70 (d, J
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= 1.8 Hz, 1H), 3.79 (s, 3H), 1.33 (s, 9H). C-NMR (100 MHz, CDCl3, 298 K) δ 162.8, 159.6,
153.0, 150.4, 144.0, 143.2, 142.8, 137.0, 136.0, 132.6, 130.3, 129.1, 128.6, 128.0, 126.2, 124.1,
121.6, 113.9, 113.7, 82.8, 55.3, 27.6. IR (thin film) νmax 2978, 1739, 1676, 1516, 1393, 1369,
1337, 1251, 1154, 876, 819, 765. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C26H24N2O5Na
467.1583; Found 467.1575.
Tertꢀbutyl (3ꢀ(4ꢀacetylphenyl)furanꢀ2ꢀcarbonyl)(quinolinꢀ8ꢀyl)carbamate (2l). The reaction was
performed according to general procedure A with 0.34 mmol 1l for 1 h. The product was isolated
after column chromatography (gradient 0ꢀ60% EtOAc in pentane) in 131 mg (82%) as a yellow
foamy solid. 1H-NMR (400 MHz, CDCl3, 298 K) δ 8.88 (dd, J = 4.2, 1.7 Hz, 1H), 8.17 (dd, J =
8.3, 1.7 Hz, 1H), 7.95–7.92 (m, 2H), 7.84–7.80 (m, 3H), 7.65 (dd, J = 7.4, 1.4 Hz, 1H), 7.60–
7.54 (m, 2H), 7.40 (dd, J = 8.3, 4.2 Hz, 1H), 6.76 (d, J =1.8, 1H), 2.58 (s, 3H), 1.32 (s, 9H). 13C-
NMR (100 MHz, CDCl3, 298 K) δ 197.7, 162.6, 152.8, 150.4, 144.0, 143.9, 143.4, 136.6, 136.5,
136.4, 136.1, 131.1, 129.12, 129.11, 128.6, 128.3, 128.2, 126.2, 121.7, 113.6, 83.1, 27.6, 26.6.
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IR (thin film) νmax 2979, 1742, 1681, 1337, 1268, 1154, 877, 819, 765. HRMS (ESI-TOF) m/z:
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[M + Na]+ Calcd for C27H24N2O5Na 479.1583; Found 479.1578.
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Methyl 4ꢀ(2ꢀ((tertꢀbutoxycarbonyl)(quinolinꢀ8ꢀyl)carbamoyl)furanꢀ3ꢀyl)benzoate (2m). The
reaction was performed according to general procedure A with 0.42 mmol 1m for 1 h. The
product was isolated after column chromatography (gradient 0ꢀ60% EtOAc in pentane) in 201
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mg (93%) as a yellow foamy solid. H-NMR (400 MHz, CDCl3, 298 K) δ 8.88 (dd, J = 4.2, 1.7
Hz, 1H), 8.17 (dd, J = 8.3, 1.7 Hz, 1H), 8.03–8.00 (m, 2H), 7.84–7.78 (m, 3H), 7.64 (dd, J = 7.4,
1.5 Hz, 1H), 7.59–7.54 (m, 2H), 7.41 (dd, J = 8.3, 4.2 Hz, 1H), 6.76 (d, J =1.8 Hz, 1H), 3.90 (s,
3H), 1.31 (s, 9H). 13C-NMR (100 MHz, CDCl3, 298 K) δ 166.8, 162.6, 152.8, 150.4, 143.92,
143.89, 143.4, 136.7, 136.3, 136.1, 131.1, 129.6, 129.5, 129.1, 128.9, 128.6, 128.2, 126.2, 121.7,
113.7, 83.1, 52.1, 27.6. IR (thin film) νmax 2981, 1740, 1721, 1679, 1337, 1276, 1154, 1113, 877,
818, 764. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C27H24N2O6Na 495.1532; Found
495.1532.
Tertꢀbutyl (3ꢀbutylthiopheneꢀ2ꢀcarbonyl)(quinolinꢀ8ꢀyl)carbamate (2n). The reaction was
performed according to general procedure A with 0.40 mmol 1n for 1 h. The product was
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isolated after column chromatography (gradient 0ꢀ30% EtOAc in pentane) in 156 mg (96%) as a
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yellow oil. H-NMR (400 MHz, CDCl3, 298 K) δ 8.89 (dd, J = 4.2, 1.7 Hz, 1H), 8.16 (dd, J =
7
8
8.3, 1.7 Hz, 1H), 7.82 (dd, J = 8.3, 1.4 Hz, 1H), 7.66 (dd, J = 7.4, 1.4 Hz, 1H), 7.56 (dd, J = 8.1,
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7.4 Hz, 1H),
7.42–7.38 (m, 2H), 6.96 (d, J = 5.1 Hz, 1H), 2.94 (t, J = 7.9 Hz, 2H), 1.70–1.58
(m, 2H), 1.46–1.35 (m, 2H), 1.30 (s, 9H), 0.92 (t, J = 7.4 Hz, 3H). 13C-NMR (100 MHz, CDCl3,
298 K) δ 167.1, 153.3, 150.3, 148.7, 144.0, 137.5, 136.0, 132.8, 129.5, 129.1, 128.7, 128.5,
128.0, 126.2, 121.6, 82.9, 32.8, 29.1, 27.6, 22.8, 14.0. IR (thin film) νmax 2958, 1733, 1678,
1337, 1252, 1155, 1115, 817, 791, 764. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C23H26N2O3SNa 433.1562; Found 433.1554.
Tertꢀbutyl (3ꢀbenzylthiopheneꢀ2ꢀcarbonyl)(quinolinꢀ8ꢀyl)carbamate (2o). The reaction was
performed according to general procedure A with 0.38 mmol 1o for 1 h. The product was
isolated after column chromatography (gradient 0ꢀ40% EtOAc in pentane) in 140 mg (80%) as a
colorless foamy solid. 1H-NMR (400 MHz, CDCl3, 298 K) δ 8.85 (dd, J = 4.2, 1.7 Hz, 1H), 8.16
(dd, J = 8.3, 1.7 Hz, 1H), 7.81 (dd, J = 8.0, 1.6 Hz, 1H), 7.60–7.52 (m, 2H), 7.40 (dd, J = 8.3, 4.2
Hz, 1H), 7.34 (d, J = 5.1 Hz, 1H), 7.32–7.27 (m, 4H), 7.24–7.18 (m, 1H), 6.79 (d, J = 5.1 Hz,
1H), 4.35 (s, 2H), 1.31 (s, 9H). 13C-NMR (100 MHz, CDCl3, 298 K) δ 166.9, 153.2, 150.3,
146.2, 144.0, 140.4, 137.4, 136.0, 133.5, 130.0, 129.2, 129.1, 128.8, 128.7, 128.4, 128.1, 126.19,
126.16, 121.7, 83.1, 35.2, 27.7. IR (thin film) νmax 2920, 1735, 1671, 1337, 1275, 1261, 1152,
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913, 764. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C26H24N2O3SNa 467.1405; Found
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467.1394.
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Tertꢀbutyl ((cis)ꢀ2ꢀphenylcyclopropaneꢀ1ꢀcarbonyl)(quinolinꢀ8ꢀyl)carbamate (2p). The reaction
was performed according to general procedure A with 0.42 mmol 1p for 2 h. The product was
isolated after column chromatography (gradient 0ꢀ50% EtOAc in pentane) in 141 mg (90%) as a
1
yellow foamy solid. Compound is racemic (single diastereomer). H-NMR (400 MHz, CDCl3,
298 K) δ 8.84 (dd, J = 3.9, 1.3 Hz, 1H), 8.09 (dd, J = 8.2, 1.3 Hz, 1H), 7.70 (d, J = 8.2 Hz, 1H),
7.39–7.18 (m, 7H + CHCl3), 6.82 (br. s, 1H), 3.37 (br. s, 1H), 2.76 (q, J = 8.2 Hz, 1H), 1.94 (q, J
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= 5.8 Hz, 1H), 1.42–1.36 (m, 1H), 1.25 (s, 9H). C-NMR (100 MHz, CDCl3, 298 K) δ 172.0,
152.9, 150.2, 144.1, 136.9, 136.8, 135.8, 129.3, 129.0, 128.7, 127.9, 127.7, 126.4, 126.0, 121.3,
82.3, 27.7, 26.7, 26.5, 11.3. IR (thin film) νmax 2978, 1736, 1695, 1390, 1368, 1295, 1267, 1155,
1042, 764. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C24H24N2O3Na 411.1685; Found
411.1675.
Nꢀ(benzo[d][1,3]dioxolꢀ5ꢀylmethyl)benzamide (3a). The reaction was performed according to
general procedure B with 1.5 equiv piperonylamine for 7 h in toluene (0.5 M with regard to 2a).
The product was isolated after column chromatography (gradient 0ꢀ40% EtOAc in pentane) in
50.5 mg (98%) as a colorless amorphous solid. The characterization data of 3a was in
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accordance with those preliminary reported in the literature.20 H-NMR (400 MHz, CDCl3, 298
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K) δ 7.79–7.75 (m, 2H), 7.51–7.45 (m, 1H), 7.45–7.37 (m, 2H), 6.84–6.75 (m, 3H), 6.48 (bs,
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1H), 5.94 (s, 2H), 4.53 (d, J = 5.6 Hz, 2H). C-NMR (100 MHz, CDCl3, 298 K) 167.3, 148.0,
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147.1, 134.4, 132.1, 131.6, 128.6, 127.0, 121.2, 108.5, 108.4, 101.1, 44.0.
Nꢀ(benzo[d][1,3]dioxolꢀ5ꢀylmethyl)ꢀ2ꢀmethylbenzamide (3b). The reaction was performed
according to general procedure B with 1.5 equiv piperonylamine for 24 h in toluene (0.5 M with
regard to 2b). This reaction furnished 3b in such a low yield that an isolation attempt was never
1
pursued. Instead, the relative ratio of compounds 1b, 2b and 3b was estimated by HꢀNMRꢀ
analysis of the crude reaction mixture.
Nꢀ(benzo[d][1,3]dioxolꢀ5ꢀylmethyl)ꢀ[1,1'ꢀbiphenyl]ꢀ2ꢀcarboxamide (3c). The reaction was
performed according to general procedure B with 1.5 equiv piperonylamine for 24 h in toluene
(0.5 M with regard to 2c). This reaction furnished 3c in such a low yield that an isolation attempt
1
was never pursued. Only traces of 3c were formed according to HꢀNMRꢀanalysis of the crude
reaction mixture.
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Nꢀ(benzo[d][1,3]dioxolꢀ5ꢀylmethyl)ꢀ3ꢀ(4ꢀmethoxyphenyl)butanamide (3d). The reaction was
performed according to general procedure B with 1.5 equiv piperonylamine for 8 h in toluene
(0.5 M with regard to 2d). The product was isolated after column chromatography (gradient 0ꢀ
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50% EtOAc in pentane) in 57.0 mg (81%) as a yellow amorphous solid. H-NMR (400 MHz,
CDCl3, 298 K) δ 7.14–7.10 (m, 2H), 6.83–6.79 (m, 2H), 6.67 (d, J = 7.9 Hz, 1H), 6.53–6.47 (m,
2H), 5.91 (s, 2H), 5.53 (br. t, 1H), 4.26 (dd, J = 14.7, 6.0 Hz, 1H), 4.15 (dd, J = 14.7, 5.5 Hz,
13
1H), 3.78 (s, 3H), 3.30–3.21 (m, 1H), 2.46–2.35 (m, 2H), 1.28 (d, J = 7.0 Hz, 3H). C-NMR
(100 MHz, CDCl3, 298 K) δ 171.5, 158.2, 147.8, 146.8, 137.7, 132.0, 127.7, 120.9, 114.0, 108.3,
108.1, 101.0, 55.2, 46.1, 43.3, 36.3, 22.1. IR (thin film) νmax 3286, 2923, 1645, 1514, 1490,
1444, 1249, 1038, 764. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C19H21NO4Na 350.1368;
Found 350.1361.
Nꢀ(benzo[d][1,3]dioxolꢀ5ꢀylmethyl)ꢀ3,3ꢀdiphenylpropanamide (3e). The reaction was performed
according to general procedure B with 1.5 equiv piperonylamine for 7 h in toluene (0.5 M with
regard to 2e). No column chromatography purification was performed for 3e, instead the product
precipitated directly from the crude reaction solution and could be obtained in 60.0 mg (84%) as
1
a colorless amorphous solid, after washing with iceꢀcold toluene. H-NMR (400 MHz, CDCl3,
298 K) δ 7.30–7.18 (m, 10H + CHCl3), 6.64 (d, J = 7.8 Hz, 1H), 6.40–6.36 (m, 2H), 5.92 (s, 2H),
5.46 (br. t, 1H), 4.60 (t, J = 7.9 Hz, 1H), 4.19 (d, J = 5.7 Hz, 2H), 2.92 (d, J = 7.9 Hz, 2H). 13C-
NMR (100 MHz, CDCl3, 298 K) δ 170.8, 147.8, 146.8, 143.5, 131.8, 128.7, 127.8, 126.6, 120.7,
108.2, 108.1, 101.0, 47.6, 43.5, 43.3. IR (thin film) νmax 3274, 2917, 1640, 1489, 1446, 1275,
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1258, 1033, 749. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C23H21NO3Na 382.1419; Found
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382.1414.
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Nꢀ(benzo[d][1,3]dioxolꢀ5ꢀylmethyl)ꢀ3ꢀphenylꢀ5ꢀ(triisopropylsilyl)pentꢀ4ꢀynamide
(3f).
The
reaction was performed according to general procedure B with 1.5 equiv piperonylamine for 8 h
in toluene (0.5 M with regard to 2f). The product was isolated after column chromatography
1
(gradient 0ꢀ50% EtOAc in pentane) in 84.0 mg (91%) as a colorless amorphous solid. H-NMR
(400 MHz, CDCl3, 298 K) δ 7.42–7.40 (m, 2H), 7.34–7.30 (m, 2H), 7.27–7.23 (m, 1H + CHCl3),
6.70 (d, J = 7.9 Hz, 1H), 6.63–6.59 (m, 2H), 5.93 (s, 2H), 5.92 (br. t, 1H), 4.38 (dd, J = 14.6, 6.2
Hz, 1H), 4.25 (dd, J = 8.2, 6.4 Hz, 1H), 4.18 (dd, J = 14.6, 5.2 Hz, 1H), 2.72 (dd, J = 14.2, 8.2
Hz, 1H), 2.59 (dd, J = 14.2, 6.4 Hz, 1H), 1.06–1.03 (m, 21H). 13C-NMR (100 MHz, CDCl3, 298
K) δ 169.7, 147.9, 147.0, 140.3, 131.8, 128.6, 127.4, 127.2, 121.1, 108.7, 108.5, 108.2, 101.1,
84.8, 46.2, 43.5, 35.6, 18.6, 11.2. IR (thin film) νmax 3287, 2942, 2864, 1642, 1504, 1490, 1444,
1275, 1254, 1042, 750. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C28H37NO3SiNa 486.2440;
Found 486.2429.
Nꢀ(benzo[d][1,3]dioxolꢀ5ꢀylmethyl)ꢀ2ꢀphenylbutanamide (3g). The reaction was performed
according to general procedure B with 1.5 equiv piperonylamine for 8 h in toluene (0.5 M with
regard to 2g). The product was isolated after column chromatography (gradient 0ꢀ60% EtOAc in
1
pentane) in 42.0 mg (71%) as a colorless amorphous solid. H-NMR (400 MHz, CDCl3, 298 K)
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δ 7.35–7.23 (m, 5H + CDCl3), 6.69 (d, J = 7.9 Hz, 1H), 6.63–6.59 (m, 2H), 5.91 (s, 2H), 5.64 (br.
t, 1H), 4.34 (dd, J = 14.7, 5.9 Hz, 1H), 4.23 (dd, J = 14.7, 5.7 Hz, 1H), 3.24 (t, J = 7.6 Hz, 1H),
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8
13
2.27–2.17 (m, 1H), 1.87–1.76 (m, 1H), 0.88 (t, J = 7.4 Hz, 3H). C-NMR (100 MHz, CDCl3,
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298 K) δ 173.3, 147.9, 146.9, 139.9, 132.2, 128.8, 128.0, 127.3, 120.8, 108.2, 108.1, 101.0, 55.3,
43.4, 26.4, 12.4. IR (thin film) νmax 3300, 2955, 1640, 1541, 1487, 1444, 1248, 1213, 1038, 805.
HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C18H19NO3Na 320.1263; Found 320.1254.
Nꢀ(benzo[d][1,3]dioxolꢀ5ꢀylmethyl)ꢀ4ꢀ(1,3ꢀdioxoisoindolinꢀ2ꢀyl)butanamide (3h). The reaction
was performed according to general procedure B with 1.5 equiv piperonylamine for 9 h in DMF
(0.5 M with regard to 2h). Prior to column chromatography purification, the reaction was diluted
with EtOAc (10 mL) and washed with brine (5 × 5 mL). The organic layer was collected, dried
over MgSO4 and concentrated in vacuo. The product was isolated after column chromatography
(gradient 0ꢀ100% EtOAc in pentane) in 53.0 mg (73%) as a colorless amorphous solid. 1H-NMR
(400 MHz, CDCl3, 298 K) δ 7.85–7.82 (m, 2H), 7.73–7.71 (m, 2H), 6.80 (s, 1H), 6.75 (m, 2H),
6.16 (br. t, 1H), 5.93 (s, 2H), 4.32 (d, J = 5.7 Hz, 2H), 3.74 (t, J = 6.2 Hz, 2H), 2.23 (t, J = 7.3
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Hz, 2H), 2.09–2.01 (m, 2H). C-NMR (100 MHz, CDCl3, 298 K) δ 171.6, 168.7, 147.9, 146.9,
134.1, 132.2, 132.0, 123.3, 121.1, 108.5, 108.3, 101.0, 43.5, 37.2, 33.8, 25.0. IR (thin film) νmax
3282, 3006, 1715, 1630, 1276, 1260, 1032, 764. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C20H18N2O5Na 389.1113; Found 389.1107.
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ethyl 6ꢀ((benzo[d][1,3]dioxolꢀ5ꢀylmethyl)amino)ꢀ2ꢀmethylꢀ2ꢀnitroꢀ6ꢀoxohexanoate (3i). The
reaction was performed according to general procedure B with 1.5 equiv piperonylamine for 9 h
in toluene (0.5 M with regard to 3i). The product was isolated after column chromatography
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(gradient 0ꢀ60% EtOAc in pentane) in 64.0 mg (88%) as a yellow oil. H-NMR (400 MHz,
CDCl3, 298 K) δ 6.74–6.69 (m, 3H), 5.94 (br. t, 1H), 5.92 (s, 2H), 4.29 (d, J = 5.8 Hz, 2H), 4.24
(q, J = 7.1 Hz, 2H), 2.27–2.15 (m, 4H), 1.77 (s, 3H), 1.76–1.66 (m, 1H), 1.60–1.49 (m, 1H), 1.26
13
(t, J = 7.1 Hz, 3H). C-NMR (100 MHz, CDCl3, 298 K) δ 171.4, 167.3, 147.9, 147.0, 132.0,
121.1, 108.4, 108.3, 101.1, 92.5, 62.9, 43.5, 35.8, 35.6, 21.1, 19.7, 13.8. IR (thin film) νmax 3284,
2898, 1744, 1642, 1547, 1488, 1249, 1182, 1035, 924, 808. HRMS (ESI-TOF) m/z: [M + Na]+
Calcd for C17H22N2O7Na 389.1325; Found 289.1319.
Nꢀ(benzo[d][1,3]dioxolꢀ5ꢀylmethyl)ꢀ3ꢀ(4ꢀchlorophenyl)ꢀ4ꢀ(1ꢀmethylꢀ1Hꢀindolꢀ3ꢀyl)butanamide
(3j). The reaction was performed according to general procedure B with 1.5 equiv
piperonylamine for 24 h in toluene (0.5 M with regard to 2j). The product was isolated after
column chromatography (gradient 10ꢀ70% EtOAc in pentane) in 72.0 mg (78%) as a yellow
foamy solid. 1H-NMR (400 MHz, CDCl3, 298 K) δ 7.52 (d, J = 8.1 Hz, 1H), 7.27–7.19 (m, 4H +
CHCl3), 7.13–7.07 (m, 3H), 6.68–6.65 (m, 2H), 6.48 (d, J = 1.3 Hz, 1H), 6.40 (dd, J = 7.9, 1.2
Hz, 1H), 5.92 (s, 2H), 5.47 (br. t, 1H), 4.22 (dd, J = 14.6, 5.9 Hz, 1H), 4.06 (dd, J = 14.6, 4.8
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Hz, 1H), 3.68 (s, 3H), 3.58–3.50 (m, 1H), 3.11–3.00 (m, 2H), 2.66 (dd, J = 14.2, 5.5 Hz, 1H),
2.37 (dd, J = 13.9, 9.6 Hz, 1H). 13C-NMR (100 MHz, CDCl3, 298 K) δ 171.1, 147.8, 146.9,
142.8, 136.9, 132.2, 132.0, 128.9, 128.6, 128.1, 127.3, 121.5, 120.8, 118.9, 118.8, 111.8, 109.2,
108.22, 108.17, 101.1, 43.21, 43.19, 43.1, 32.6, 32.0. IR (thin film) νmax 3287, 2916, 1642, 1490,
1444, 1253, 1039, 747. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C27H25ClN2O3Na
483.1451; Found 483.1446.
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Nꢀ(benzo[d][1,3]dioxolꢀ5ꢀylmethyl)ꢀ3ꢀ(4ꢀmethoxyphenyl)furanꢀ2ꢀcarboxamide
(3k).
The
reaction was performed according to general procedure B with 1.5 equiv piperonylamine for 8 h
in toluene (0.5 M with regard to 2k). The product was isolated after column chromatography
1
(gradient 0ꢀ60% EtOAc in pentane) in 64.0 mg (91%) as a colorless amorphous solid. H-NMR
(400 MHz, CDCl3, 298 K) δ 7.70–7.65 (m, 2H), 7.41 (d, J = 1.8 Hz, 1H), 6.95–6.92 (m, 2H),
6.82–6.74 (m, 3H), 6.60 (d, J = 1.8 Hz, 1H), 6.57 (br. t, 1H), 5.94 (s, 2H), 4.48 (d, J = 5.8 Hz,
2H), 3.83 (s, 3H). 13C-NMR (100 MHz, CDCl3, 298 K) δ 159.6, 158.7, 147.9, 147.0, 142.7,
141.0, 132.1, 131.0, 130.7, 124.0, 121.2, 114.4, 113.6, 108.5, 108.3, 101.1, 55.3, 42.9. IR (thin
film) νmax 3290, 2932, 1655, 1516, 1489, 1249, 1179, 1037, 936, 834, 780. HRMS (ESI-TOF)
m/z: [M + Na]+ Calcd for C20H17NO5Na 374.1004; Found 374.0994.
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3ꢀ(4ꢀAcetylphenyl)ꢀNꢀ(benzo[d][1,3]dioxolꢀ5ꢀylmethyl)furanꢀ2ꢀcarboxamide (3l). The reaction
was performed according to general procedure B with 1.5 equiv piperonylamine for 9 h in
toluene (0.5 M with regard to 2l). The product was isolated after column chromatography
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(gradient 0ꢀ60% EtOAc in pentane) in 63.0 mg (87%) as a colorless amorphous solid. H-NMR
(400 MHz, CDCl3, 298 K) δ 8.00–7.97 (m, 2H), 7.83–7.80 (m, 2H), 7.45 (d, J = 1.8 Hz, 1H),
6.82–6.74 (m, 3H), 6.70 (br. t, 1H), 6.66 (d, J = 1.8 Hz, 1H), 5.94 (s, 2H), 4.48 (d, J = 5.9 Hz,
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2H), 2.61 (s, 3H). C-NMR (100 MHz, CDCl3, 298 K) δ 197.8, 158.3, 148.0, 147.1, 143.0,
141.9, 136.6, 136.4, 131.8, 130.3, 129.7, 128.1, 121.3, 114.3, 108.5, 108.4, 101.1, 43.0, 26.7. IR
(thin film) νmax 3336, 2917, 1677, 1524, 1489, 1260, 1039, 937, 843, 764. HRMS (ESI-TOF)
m/z: [M + Na]+ Calcd for C21H17NO5Na 386.1004; Found 386.0995.
Methyl 4ꢀ(2ꢀ((benzo[d][1,3]dioxolꢀ5ꢀylmethyl)carbamoyl)furanꢀ3ꢀyl)benzoate (3m). The
reaction was performed according to general procedure B with 1.5 equiv piperonylamine for 9 h
in toluene (0.5 M with regard to 2m). The product was isolated after column chromatography
1
(gradient 0ꢀ60% EtOAc in pentane) in 67.0 mg (88%) as a colorless amorphous solid. H-NMR
(400 MHz, CDCl3, 298 K) δ 8.08–8.05 (m, 2H), 7.81–7.78 (m, 2H), 7.44 (d, J = 1.8 Hz, 1H),
6.82–6.74 (m, 3H), 6.67 (br. t, 1H), 6.65 (d, J = 1.8 Hz, 1H), 5.94 (s, 2H), 4.48 (d, J = 5.8 Hz,
2H), 3.92 (s, 3H). 13C-NMR (100 MHz, CDCl3, 298 K) δ 166.9, 158.3, 148.0, 147.1, 143.0,
141.9, 136.4, 131.8, 130.3, 129.6, 129.5, 129.4, 121.3, 114.4, 108.5, 108.4, 101.1, 52.1, 43.0. IR
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