Cross-Coupling of Amide and Amide Derivatives to Umbelliferone Nonaflates: Synthesis of Coumarin Derivatives and Fluorescent Materials

Article abstract of DOI:10.1021/acs.joc.0c00813

The Buchwald-Hartwig cross-coupling reaction between 4-methylumbelliferone-derived nonaflates with amides, carbamates, and sulfonamides is described. A wide variety of N-substituted 7-amino coumarin analogues was prepared in good to excellent yields. The photophysical properties of aqueous-soluble derivatives were determined, and they displayed auxochrome-based variations. Gram-scale synthesis provided an acrylamide analogue, which was used to fabricate a fluorescent poly(2-hydroxylethyl methacrylate) (pHEMA) hydrogel that was resistant to leaching in ultrapure H2O. We envisage that our reported protocol to access 7-amino-4-methylcoumarin derivatives will find use toward the development of new fluorescent coumarin-based probes by researchers in the field.

Full text of DOI:10.1021/acs.joc.0c00813

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Article
Cross-coupling of amide and amide derivatives to umbelliferone
nonaflates: synthesis of coumarin derivatives and fluorescent materials.
Shane Hickey, Samuel Nitschke, Martin Jay Sweetman, Christopher
J. Sumby, Douglas A. Brooks, Sally E Plush, and Trent D. Ashton
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00813 • Publication Date (Web): 19 May 2020
Downloaded from pubs.acs.org on May 19, 2020
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Cross-coupling of amide and amide derivatives to umbelliferone
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nonaflates: synthesis of coumarin derivatives and fluorescent materials
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Shane M. Hickey,a Samuel O. Nitschke,a Martin J. Sweetman,a Christopher J. Sumby,b Douglas
A. Brooks,a Sally E. Plush,a and Trent D. Ashton*c,d
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aUniversity of South Australia, Clinical Health Sciences, Cancer Research Institute, SA, 5000, Australia
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Department of Chemistry, The University of Adelaide, Adelaide, SA, 5005, Australia
c
The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia
dDepartment of Medical Biology, The University of Melbourne, Parkville 3010, Australia
E-mail: ashton.t@wehi.edu.au
Keywords
Cross-coupling, palladium, Buchwald-Hartwig, umbelliferone, coumarin, fluorescence,
hydrogel.
Abstract
The Buchwald-Hartwig cross-coupling reaction between 4-methylumbelliferone derived
nonaflates with amides, carbamates, and sulfonamides is described. A wide variety of N-
substituted 7-amino coumarin analogues were prepared in good to excellent yields. The
photophysical properties of aqueous soluble derivatives were determined and displayed
auxochrome based variations. Gram scale synthesis provided an acrylamide analogue which
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was used to fabricate a fluorescent poly(2-hydroxylethyl methacrylate) (pHEMA) hydrogel
that was resistant to leaching in ultrapure H2O. We envisage our reported protocol to access 4-
methylumbelliferone derivatives will find use towards the development of new fluorescent
coumarin-based probes by researchers in the field.
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Introduction
Fluorogenic materials are essential tools in chemical biology,1 biochemical and cellular
assays,2,3 and analyte sensing.4,5 Coumarins, such as 7-amino-4-methylcoumarin (AMC), are
frequently employed as reporters for these applications; by masking the amine as an amide the
donor-acceptor system properties are altered and the fluorescent signal from AMC is perturbed.
Fluorogenic probes are commonly designed using this masking strategy, often through the
conjugation of a small peptide to the amine, which upon cleavage under assay conditions (e.g.
enzymatic cleavage) restores the fluorescence intensity.6 In addition to frequently appearing as
a scaffold in medicinal chemistry studies,7-10 functionalised coumarins have been investigated
in a number of contexts. For example, benzamide 1 (Figure 1) has been investigated as a probe
to monitor cationic photopolymerization reactions.11 Although long-established,12,13
sulfonamidyl coumarins were recently highlighted by Sharma et al. as a neglected fluorophore;
as such, compound 2 was prepared and characterised to demonstrate photophysical properties
equivalent to that of AMC in phosphate buffered saline at pH 7.4.14 Additionally, the 4-
nitrobenzylcarbamate 3 was prepared to investigate nitroreductase activity in bacteria such as
methicillin-resistant Staphylococcus aureus (MRSA).15 Classically, AMC is synthesised using
a three-step procedure and then functionalised using acyl10 or sulfonyl halides.14 Amide
coupling reagents are also used to generate analogues, but standard reagents are not always
effective.13,16
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Figure 1. Representative examples of amide, sulfonamide and carbamate substituted coumarins.
The Buchwald-Hartwig cross-coupling reaction has recently emerged as a powerful and
indispensable tool for the synthesis of fluorescent probes and has unlocked molecules that are
synthetically challenging using traditional methods. This approach has been demonstrated in
rhodamine (e.g. the azetidine auxochrome)17-19 and 1,8-naphthalimide fluorophore
development.17,20-24 The power of the Buchwald-Hartwig cross-coupling methodology stems
from the ability to incorporate amines, amides, carbamates and sulfonamides in a single (often
terminal) synthetic transformation from common intermediates.25-28
The substitution of amine auxochromes into coumarin systems has been achieved using
Buchwald-Hartwig methodology to install amines and anilines.29,30 Due to a lack of suitable
syntheses of halogenated coumarins,30 the 7-hydroxy coumarins derived from Pechmann
condensations are typically converted to the triflate for use as the electrophilic coupling partner.
However, triflates are susceptible to hydrolysis and sometimes require high catalyst loadings
in order to generate favourable conversion to product.18,31,32 The related coumarin nonaflate, a
more hydrolytically stable sulfonate,33 has been exploited by the Bodke group for a number of
cross-coupling reactions including Buchwald-Hartwig aminations,34 Suzuki,35 and
Sonogashira.36 Aside from an isolated example of cross-coupling with acetamide31 and another
report using sulfonamides,32 there are no investigations detailing Buchwald-Hartwig cross-
coupling conditions that facilitate the incorporation of amides and related functional groups
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directly onto the coumarin with demonstrated substrate scope. This work establishes a synthetic
procedure to access a broad range of amide, carbamate and sulfonamide substituted coumarins
from the corresponding nonaflates using Buchwald-Hartwig cross-coupling conditions.
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Results and Discussion
Synthesis
The synthesis of 5 proceeded in a straightforward manner; treatment of 4-methylumbelliferone
(4, Scheme 1) with nonafluorobutanesulfonyl fluoride (NfF, 1.1 equiv.) and K2CO3 (1.5 equiv.)
in MeCN at ambient temperature for 2 hours lead to full conversion and precipitation of 5 from
solution. Dilution of the reaction mixture with H2O and isolation using vacuum filtration
afforded 5 in excellent yield (95%) as an easy to handle powder which was bench-stable for
extended periods (>18 months, as evidenced by NMR and HPLC analysis).
Scheme 1. Synthesis of nonaflate starting material.
Nonaflate 5 and benzamide as model substrates were used to investigate the reaction conditions
(Table 1) which were based upon those reported by Joy et al. who successfully coupled anilines
and pyridinones to 5.34 Treatment of nonaflate 5 with benzamide (1.2 equiv., Entry 1) in the
presence of G3-Pd-xantphos (1 mol%) and Cs2CO3 (1.4 equiv.) in 1,4-dioxane (1 mL per
0.1 mmol of 5) at 100 °C led to full consumption of the starting material after 22 hours and
compound 1 was isolated in 22% yield using column chromatography. The low yield of 1 was
partially attributed to limited compound solubility in the solvent mixtures required for column
chromatography and potential decomposition on silica gel which was indicated by two-
dimensional TLC. For the remaining entries in Table 1 compound 1 was isolated by trituration
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using Et2O. Unlike reports from Bodke,34-36 we found that the addition of fluoride (as TBAF)
resulted in sulfonate hydrolysis as the dominant reaction while no cross-coupling product was
observed (Entry 2). A modest increase in yield of amide 1 (38%, Entry 3) was achieved when
using 2.0 equivalents of Cs2CO3.
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Table 1. Optimisation of reaction conditions.
Entry BzNH2
(equiv.)
G3-Pd-L
(mol%)
Base
Solvent
(M)
T
t
Yield
(%)
22a
0c
(equiv.)
(°C)
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(h)
22
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1
2b
3
1.2
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1.2
1.2
1.2
1.2
1.2
2.0d
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
xantphos (1)
Cs2CO3 (1.4) 1,4-Dioxane (0.1)
Cs2CO3 (1.4) 1,4-Dioxane (0.1)
Cs2CO3 (2.0) 1,4-Dioxane (0.1)
Cs2CO3 (2.0) 1,4-Dioxane (0.1)
Cs2CO3 (2.0) 1,4-Dioxane (0.1)
Cs2CO3 (2.0) 1,4-Dioxane (0.1)
Cs2CO3 (2.0) 1,4-Dioxane (0.1)
Cs2CO3 (2.0) 1,4-Dioxane (0.1)
xantphos (1)
xantphos (1)
38
0c
4
DPPF (1)
5
JackiePhos (1)
t-BuBrettPhos (1)
t-BuXPhos (1)
t-BuXPhos (1)
t-BuXPhos (1)
t-BuXPhos (1)
t-BuXPhos (1)
t-BuXPhos (1)
t-BuXPhos (1)
t-BuXPhos (1)
t-BuXPhos (1)
t-BuXPhos (1)
t-BuXPhos (1)
t-BuXPhos (1)
t-BuXPhos (1)
35
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24
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67
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85
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59
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K2CO3 (2.0)
K3PO4 (2.0)
1,4-Dioxane (0.1)
1,4-Dioxane (0.1)
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K3PO4 (3.0)d 1,4-Dioxane (0.1)
K3PO4 (2.0)
K3PO4 (2.0)
K3PO4 (2.0)
K3PO4 (2.0)
K3PO4 (2.0)
K3PO4 (2.0)
K3PO4 (2.0)
K3PO4 (2.0)
PhMe (0.1)
i-PrOH (0.1)
t-BuOH (0.1)
PhMe (0.2)
PhMe (0.4)
PhMe (0.6)
t-BuOH (0.4)
i-PrOH (0.4)
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100
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a) Purified using column chromatography; b) 2.0 equivalents of TBAF were used; c) Compound 4 was the
major product; d) Drying of the reagent did not improve the yield; e) Conducted on a 1.5 mmol scale. All other
reaction performed at 0.5 mmol.
When G3-Pd-dppf was used in place of G3-Pd-xantphos (Table 1, Entry 4) the formation of 1
was not observed, instead, the isolated material was predominantly 4-methylumbelliferone (4).
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Biaryl phosphine ligands were then trialled: G3-Pd-JackiePhos (Entry 5) effected the formation
of 1 in 35% yield whereas t-BrettPhos and t-BuXPhos ligands (used as G3-precatalysts) both
afforded the product in 59% yield (Entries 6 and 7). Given the relative cost, but comparable
performance of the t-BrettPhos and t-BuXPhos ligands, the use of G3-Pd-t-BuXPhos was
favoured for this investigation.
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When the reaction was performed using 2.0 equivalents of BzNH2 (Entry 8) the yield of 1 was
reduced to 24%. A lower yield of 1 (42%, Entry 9) was obtained using K2CO3 (2.0 equiv.),
while K3PO4 (2.0 equiv.) gave a comparable yield of 1 (61%, Entry 10) to that obtained when
Cs2CO3 was employed. On the basis of relative cost between K3PO4 and Cs2CO3, the use of
the former was favoured. When 3.0 equivalents of K3PO4 were used, a decreased yield was
obtained (24%, Entry 11). PhMe at 100 °C was found to be a suitable solvent for this
transformation giving the benzamide product in 67% yield after 16 hours (Entry 12). Similar
results were obtained using i-PrOH and t-BuOH (64 and 59%, Entries 13 and 14, respectively)
despite the reactions being conducted at a lower temperature. No product was obtained when
trial reactions were performed in DMF, DMSO or MeCN.
Finally, performing the reaction at higher concentration led to improved yields; at 0.2 M and
0.4 M of 5 in PhMe, the product was isolated in 70 and 85% yield, respectively (Entries 15 and
16). A yield of 79% was obtained when the reaction was performed at 0.6 M in PhMe, however
at this concentration the reaction becomes impractical due to difficulties with stirring.
Prompted by this observation, we reinvestigated the reaction at 0.4 M in t-BuOH, which gave
a modest improvement in yield to 74% (Entry 18) compared with the reaction performed at 0.1
M. A slight decrease in yield of 1 (59%) was obtained when carrying out the reaction in i-PrOH
at a concentration of 0.4 M (Entry 19) compared to the more dilute conditions (Entry 13).
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With reliable conditions in hand (Entry 16), the reaction scope was investigated using a
representative set of amides. The cross-coupling reaction with 4-fluorobenzamide proceeded
efficiently to give 6 in 91% yield (Scheme 2). However, more electron deficient 4-
trifluoromethyl or 4-nitrobenzamides gave lower yields of amides 7 and 8 (59 and 31%,
respectively). Conversely, using the electron rich 4-methoxybenzamide gave 9 in a 92% yield.
Substitution in the 2-position of the benzamide was tolerated with 2-fluorobenzamide giving
10 in a modest yield of 66%, while 2-methyl 11 and 2-methoxy derivatives 12 were isolated in
high yields (88 and 92%, respectively). Both 3-fluoro and 3-methoxybenzamides were
incorporated in good yields giving 13 and 14 in 92 and 79% yield, respectively. The 3,5-
dimethoxy 15 and 3,5-dintiro 16 analogues were isolated in 43 and 37% yield, respectively. It
is noteworthy that the commercially available 3,5-dimethoxybenzamide required
recrystallisation prior to use or no product formation was observed.
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Scheme 2. Reagents and conditions: 5 (0.50 mmol), amide (1.2 equiv.), G3-Pd-t-BuXPhos (1–2 mol%), K3PO4
(2.0 equiv.), PhMe (2.6 mL per mmol), 100 °C, 16–48 h.; a) G3-Pd-t-BuBrettPhos (1 mol%) was used in place of
G3-Pd-t-BuXPhos; b) The reaction was performed using 1 gram (2.2 mmol) of 5.
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In general, benzamides gave high yields of the desired product, although lower yields were
obtained in the presence of strong electron withdrawing substituents. The reduced
nucleophilicity of these benzamides likely hinders transmetalation on the Pd(II) oxidative
addition species.37 Based on results obtained during our optimisation (Table 1 Entry 6 cf Entry
7) and reported superiority the t-BuBrettPhos ligand was investigated for the synthesis of 7 and
8.27,38,39 In both instances a modest increase in yield was found using G3-Pd-t-BuBrettPhos (1
mol%): compound 7 was isolated in 68%, while 8 was still prepared in low yield (34%).
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Pyridyl 4- and 3-carboxamides reacted smoothly giving amides 17 and 18 in 99 and 93% yield,
respectively. The cross-coupling of 5 with pyridine-2-carboxamide afforded 19 in 12% yield;
a result which is in keeping with previous reports.22 Acrylamide 20 was produced in 82% yield
when performed on a 0.5 mmol scale; conducting the reaction on a gram scale (2.2 mmol of 5)
gave 20 in 90% yield. Reactions performed using propanamide with either the t-BuXPhos or t-
BuBrettPhos ligand gave 21 in high yield (83 and 81%, respectively) while 22 was obtained in
54% yield. For the aliphatic amides significant hydrolysis was observed during the standard
work-up procedure; acidification with saturated KH2PO4 (pH 5) prior to dilution with H2O
prevented this loss. The isolation of 23 from the crude mixture by trituration with MeOH
resulted in some product loss and low yield (25%).
Ethyl oxamate was introduced to give the phosphate reactive coumarin 24 in 94% yield
(Scheme 3),40 while tert-butyl carbamate was installed in 55% yield providing the masked 7-
amino coumarin 25, which itself, can be converted to benzamide analogues using [RhCl(cod)]2
and arylboroxines.41 Similarly, benzyl carbamate was successfully coupled to give Cbz-
protected analogue 26 in 71% yield. Substituted benzyl carbamates such as 4-nitrobenzyl
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carbamate and 4-chlorobenzyl carbamate were added to the coumarin scaffold to give the
corresponding fluorogenic compounds 3 and 27 in 87 and 46% yield, respectively. The latter
example provides a synthetic handle for further elaboration and could be applied to the
synthesis of fluorogenic probes with self-immolative linkers.42 A cholesterol derived
carbamate was also a suitable cross-coupling partner giving 28 in 69% yield.
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Scheme 3. Reagents and conditions: 5 (0.5 mmol), nucleophile: oxamate, carbamate or sulfonamide (1.2 equiv.),
G3-Pd-t-BuXPhos (1–2 mol%), K3PO4 (2.0 equiv.), PhMe (2.6 mL per mmol), 100 °C, 16–48 h.
Alkyl sulfonamides were found to be good substrates for the cross-coupling reaction with 5;
methanesulfonamide and tert-butylsulfonamide gave 29 and 30 in 92 and 77% yield,
respectively (Scheme 3). Reactions employing benzenesulfonamides were not as productive as
the related benzamides shown in Scheme 1, and they also displayed sensitivity to arene
substitution. The unsubstituted derivative 31 was isolated in 30% following the standard
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conditions and similar results were obtained using 4-chloro and 4-(trifluoromethyl)benzene
sulfonamide giving 32 and 33 in 30 and 37% yield, respectively. Conversely, the reaction using
4-nitrobenzene sulfonamide gave the desired coumarin 34 in 72% yield. Similarly, the presence
of a weakly electron withdrawing 3-methoxy substituent gave the corresponding product 35 in
good yield (68%).
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To investigate the modularity of this approach, reactions between substituted coumarin
nonaflates and 2-methoxybenzamide were performed. When a trifluoromethyl group was
present in the 4-position of the coumarin the reaction gave the desired amide 39 in a modest
51% yield (Scheme 4). The presence of an ethyl ester at the 3-position of the coumarin scaffold
adversely impacted the yield obtained for the cross-coupling product 40 (6%) compared to 92%
for the 4-methyl analogue (12, Scheme 2). Similarly, a low yield (16%) of 41 was obtained
when the nonaflate was in the 6-position of the coumarin framework; this was improved to
45% using G3-Pd-t-BuBrettPhos. These results highlight the need to develop this chemistry
and identify the scope and limitations governed by the inherent reactivity of the coupling
partners.
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Scheme 4. Reagents and conditions: 39–41 (0.5 mmol), 2-methoxybenzamide (1.2 equiv.), G3-Pd-t-BuXPhos (1
mol%), K3PO4 (2.0 equiv.), PhMe (2.6 mL per mmol), 100 °C, 16–48 h.; a) G3-Pd-t-BuBrettPhos (1 mol%) was
used in place of G3-Pd-t-BuXPhos.
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Photophysical Characterisation
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For all compounds which were soluble in 1% DMSO in H2O (ca. pH = 8), key photophysical
properties were determined (Table 2) to provide an insight into their potential application as
probes in aqueous environments. The absorption maxima measured for most of the 7-
substituted derivatives is independent of structure and are in the range of 321–331 nm. The
presence of the 4-trifluoromethyl moiety of 39 exhibited an anticipated change in absorbance
to 340 nm (Entry 15) when compared with the 4-methyl scaffold.43 Additionally, the 6-amide
substituted coumarin 41 had an absorbance maximum at 265 nm (Entry 16), which results from
a lack of conjugation of the 6-substituent, and is more characteristic of an unsubstituted
coumarin,44 despite the near planarity of the compound in the solid state (Figure 2). In addition
to the expected reduced conjugation from a nitrogen lone pair in the 6-position, further
explanation for the absence of a strong charge transfer band in the absorbance spectra of 41
can be derived from the single crystal X-ray structure (Figure 2). The C-N bond length between
the amide and the coumarin (1.473(2) Å) is notably longer than the distance measured for the
one other 6-amide substituted coumarin45 reported in the Cambridge Structural Database (CSD,
accessed 16/01/2020, C-N distance 1.434(2) Å) and considerably longer than the equivalent
distance in the eleven 7-amide substituted coumarin derivatives (C-N bond distance range
1.385(3)–1.418(9) Å; mean 1.40 Å) also reported in the CSD.46-48 Additionally, the N-C
distance (1.309(2) Å) measured between the nitrogen and carbonyl carbon, indicates strong
delocalisation of the nitrogen lone pair within the amide bond rather than into the π-system of
the coumarin as observed for other 6- and 7-amide substituted coumarins (mean amide bond
length 1.37 Å).
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Table 2. Photophysical data of coumarin derivatives in 1% DMSO in H2O.
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Entry Compound Absorption Properties
Emission Properties
Stokes shift ΦF
(nm)
(cm-1)
108
λabs
(nm)
εmax
λem
(nm)
430
420
443
445
432
396
402
398
399
403
458
458
458
458
434
441
Brightness
(M-1 cm-1)
500
(M-1 cm-1)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1
322
8,300
7,800
6,678
8,101
8,109
7,433
4,959
5,612
5,644
5,707
5,767
9,319
9,126
9,319
9,222
6,370
15,060
0.06
9
11
12
17
18
19
20
21
22
25
29
30
31
33
39
41
328
326
327
327
331
328
325
325
327
321
323
321
322
340
265
11,000
3,300
7,900
5,500
3,900
8,500
15,000
4,800
15,600
7,100
13,400
13,000
11,000
3,600
7,100
92
117
118
105
65
0.06
0.09
0.03
<0.01
<0.01
<0.01
0.71
0.68
0.94
0.49
0.48
0.55
0.02
0.07
0.05
600
300
300
30
30
50
10
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60
74
73
74
76
10,700
3,200
14,600
3,500
6,400
7,100
200
137
135
137
136
94
200
300
176
Figure 2. Crystal structure of 41. Thermal ellipsoids are shown at the 50% confidence interval. Inset: enlarged
view of the amide with key distances highlighted.
The emission maxima for amide analogues were observed between 399–445 nm. Subtle
variations of the emission wavelength were demonstrated between the unsubstituted benzamide
1 (λem 430 nm), 2-methylbenzamide 11 (λem 420 nm) and the 2-methoxybenzamide derivative
12 (λem 443 nm); however, all displayed low quantum yield (ΦF <0.10). The emission maxima
also varied for the pyridine regioisomers with the 4-pyridine 17 and 3-pyridinecarboxamide 18
analogues emitting blue light (λem 445 and 432 nm, respectively), while the 2-pyridyl analogue
gave a purple emission (λem 392 nm). In contrast to the benzamide analogues, the propyl and
butyl amides 21 and 22 displayed similar absorption and emission properties to the 2-pyridyl
system but with enhanced quantum yields (ΦF 0.71 and 0.68, respectively). The tert-butyl
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carbamate protected analogue 25 (Entry 10) was the brightest compound in this series;
excitation at the absorbance maxima (λabs 327 nm, εmax 15,600 M-1 cm-1) results in emission at
403 nm with a quantum yield of 0.94 resulting in a brightness of 14,600 M-1 cm-1. The quantum
yield of 25 decreases in DMSO (49%), CHCl3 (32%) and PhCH3 (4%) (Table S2) which could
be suggestive of an aggregate induced emission.
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The sulfonamide derivatives 29–31 and 33 (Entries 12–15) all demonstrated maximal emission
of 458 nm (λex ~320 nm) with a shoulder at ~390 nm, as opposed to all other derivatives whose
absorption bands were structureless (see ESI for spectra). To investigate this further, a pH
titration was conducted on compound 30 at 50 µM between pH 3–9. As the pH of the solution
increased, the absorption band at 322 nm decreased while the band at 355 nm increased (Figure
3). An isosbestic point was observed at approximately 331 nm and a pKa of 8.2 was calculated
for compound 30. When excited at 322 nm, the emission spectra of 30 showed a decline in the
395 nm band and an increase in the 470 nm band as the pH was increased. Furthermore, the
pH responsiveness was reversible with the reverse titration from pH 9 to 3 strongly matching
the data shown in Figure 4 (see ESI for spectra). This data suggests that the observed shoulder
in Figures S178 and S179 (sulfonamides 29 and 30, respectively) are due to the presence of
both protonated and deprotonated species which exist at pH 8 in the 1% DMSO in H2O;
consistent with previous reports.13 Similar to the observations by Sharma et al.,14 the
sulfonamide analogues typically displayed good quantum yields (ΦF ~0.50, λex ~320 nm, λem
458 nm) for alkyl (29 and 30) and benzene (31) derivatives. The presence of the 4-
trifluoromethyl group in the benzene sulfonamide derivative 33 resulted in reduced efficiency
(ΦF 0.02) despite similar absorption and emission properties (λabs 322 nm, εmax 11,000 M-1 cm-1,
λem 458 nm) to 31.
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Figure 3. pH titration of compound 30 (50 µM) over a pH range of 3–9 in a 10 mM NaCl solution. a) absorption
spectra; b) absorption versus pH at 322 and 355 nm; c) emission spectra (λex = 322 nm); and d) emission intensity
versus pH at 395 and 470 nm.
These results demonstrate the impact of subtle auxochrome structural variations on the
photophysical properties of coumarin compounds. Notably, the high quantum yields for several
of the analogues in aqueous conditions, where typical organic fluorophores undergo significant
non-radiative decay, suggest that these types of compounds could find use in aqueous sensing
applications. Furthermore, the operationally simple Buchwald-Hartwig protocol described
should make this family of compounds readily accessible to those interested.
Hydrogel Formation
Given the relatively high quantum efficiency and brightness of the aliphatic amide coumarins
(Table 2, Entries 8 and 9) we envisaged that the practically non-fluorescent acrylamide
analogue (20) would be a suitable reagent for the fabrication of leach-resistant fluorescent
cross-linked polymer materials. With this in mind, copolymerisation of 20 with 2-
hydroxylethyl methacrylate and ethylene glycol dimethacrylate (crosslinker) was performed to
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prepare a coumarin poly(2-hydroxylethyl methacrylate) (pHEMA) derived hydrogel 20-
pHEMA (see ESI for synthesis details). Two hydrogels were also prepared as controls; one in
the absence of a fluorophore (pHEMA) and one in the presence of propanamide 22,49 which is
not competent in radical polymerisation reactions, to give 22-pHEMA. Each method gave
hydrogels that were transparent in visible light (Figure 4A). Both 20-pHEMA and 22-pHEMA
gave detectable fluorescence upon irradiation at 365 nm (Figure 4B) while the non-fluorescent
control performed as expected with no observable emission. The intense visible fluorescence
of the acrylamide (20) derived gel was an indication of successful cross-linking as the
acrylamide itself is essentially non-fluorescent with a brightness of 50 M-1 cm-1 (Table 2, Entry
7). Effective cross-linking of the acrylamide 20 polymer was demonstrated by its relative
resistance to leaching in ultrapure H2O (Figure 4C). After soaking for 20 hours, the cross-
linking gel displayed no change in fluorescence intensity. In contrast, the 22-pHEMA exhibited
a decrease in fluorescent intensity of 12% over the same period, indicating that the non-
covalently linked coumarin leached out of the gel matrix.
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Figure 4. a) and b) show photographs of the fabricated hydrogels illuminated by white and UV (365 nm) light
respectively. From left to right the hydrogels are; 20-pHEMA, 22-pHEMA, and pHEMA; c) shows the decrease
in fluorescence intensity from the 20-pHEMA and 22-pHEMA following a 20 h soak in 1 L ultrapure H2O. A
decrease of 0.86 and 11.95% was measured for 20-pHEMA and 22-pHEMA, respectively.
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Conclusion
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The Buchwald-Hartwig cross-coupling reported herein contributes to the growing toolbox for
fluorophore synthesis. The bench-stable and easily synthesised hydroxy coumarin derived
nonaflates were suitable substrates for the incorporation of a variety of amide, carbamate, and
sulfonamide nucleophiles in good to excellent yields. Some aliphatic amides and electron
deficient coumarin scaffolds were found to be less competent substrates for the reaction, but in
most cases still gave isolatable product. The photophysical properties of all aqueous soluble
analogues prepared were established. The aliphatic amides investigated displayed good
quantum yields (ΦF >0.60) while a boc-protected 7-amino-4-methylcoumarin 25 was
surprisingly bright (14,600 M-1 cm-1) with a purple emission (λem 403 nm, λex 327 nm, ΦF 0.94)
in 1% DMSO in H2O. Conversely, the benzamide analogues were typically non-fluorescent.
Sulfonamide substituted 4-methyl coumarins were typically efficient fluorophores (ΦF ~ 0.50,
λex ~320 nm, λem 458 nm). Furthermore, the sulfonamide proton was found to be more acidic
compared to their amide counterparts; tert-butylsulfonamide 30 has a pKa of approximately
8.2. Finally, a non-fluorescent acrylamide derived coumarin 20 was prepared in a gram-scale
reaction and found to be a suitable monomer for the preparation of a fluorescent and leach-
resistant cross-linked polymer hydrogel 20-pHEMA. We envisage that our reported conditions
to generate 4-methylumbelliferone derivatives will be of great use to researchers wanting to
access coumarin-based probes for an array of fluorogenic applications.
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Experimental
Unless otherwise indicated all reagents were used as purchased from commercial sources.
Purification of 3,5-dimethoxybenzamide was achieved by recrystallisation from hot CHCl3/n-
hexane. Anhydrous PhMe and MeCN was obtained by drying over freshly activated 3 Å
molecular sieves. Thin layer chromatography (TLC) was performed on silica gel 60 F254 plates
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purchased from Merck (Australia). All reactions performed at elevated temperatures were
conducted using a heating mantle. All melting points were obtained using a digital ISG®
melting point apparatus and are uncorrected. All 1H, 13C and 19F NMR spectra were collected
on a BRUKER AVANCE III 500 MHz FT-NMR spectrometer. All NMR experiments were
performed at 25 °C. 2D NMR experiments were performed on most compounds to ensure
correct characterisation and can be provided upon request. Samples were dissolved in either
CDCl3 or DMSO-d6, with the residual solvent peak used as the internal reference—CDCl3;
7.26 (1H) and 77.0 (13C), DMSO-d6; 2.50 (1H) and 39.52 (13C).50 Fluorine spectra are externally
referenced using 0.05% α,α,α-trifluorotoluene in CDCl3; −63.72 (19F). High resolution mass
spectral data was collected using an AB SCIEX TripleTOF 5600 mass spectrometer in a 95%
MeOH in H2O solvent system containing 0.1% formic acid. Analyte solutions were prepared
in HPLC grade methanol (conc. ~1 mg mL-1). RP-HPLC experiments were conducted on a
Shimadzu Prominence UltraFast Liquid Chromatography (UFLC) system equipped with a
CBM-20A communications bus module, a DGU-20ASR degassing unit, an LC-20AD liquid
chromatograph pump, an SIL-20AHT autosa-sampler, and SPD-M20A photo diode array
detector, a CTO-20A column oven and a Phenomenex Kinetex 5 mM C18 100 Å
250 mm × 4.60 mm column. The solvent system used was a gradient beginning at 5% MeOH
in H2O containing 0.1% formic acid over 8 min, followed by 50% MeOH in H2O containing
0.1% formic acid over 2 min, followed by 95% MeOH in H2O containing 0.1% formic acid
over 5 min. A flow rate of 1 mL min-1 was maintained throughout. UV-Vis spectra were
recorded over the range of 200–800 nm on a Varian Cary 50 UV-Vis spectrophotometer
(Agilent) in a 10 mm pathlength quartz cuvette. A 1% DMSO solution was used for
background correction for all synthesised compounds except for pH titrations where a 0.01 M
NaCl solution was used. For quinine sulfate, 0.1 M H2SO4 was used for background correction.
Fluorescence spectra were recorded on a Varian Cary Eclipse spectrophotometer (Agilent) over
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315–600 nm. Excitation and emission slit widths were set at 2.5 nm each and a 10 mm
pathlength quartz cuvette was used for all experiments. A 1% DMSO solution was used for
background correction for all synthesised compounds except for pH titrations where a 0.01 M
NaCl solution was used. For quinine sulfate, 0.1 M H2SO4 was used for background correction.
Fluorescence quantum yields were determined by the comparative method using quinine
sulfate as the reference standard (ΦF = 0.54 in 0.1 M H2SO4). A concentration series for each
compound was prepared in 1% DMSO, from a 0.01 M stock solution of each compound in
DMSO. The concentration series were prepared such that the maximum and minimum
absorbencies fell between 0.10 and 0.01. pH measurements of compound 30 were determined
using a pre-calibrated Orion Ross pH meter. Absorbance and fluorescence measurements were
performed as described previously. Boiled ultra-pure H2O was used to prepare all aqueous
solutions. A stock solution of 30 was prepared in DMSO (10 mM) which was diluted to 50 µM
using aqueous 10 mM NaCl. The pH was adjusted to the stirring solution of 30 using dilute
HCl and NaOH solutions. Care was taken to minimise the amount of acid/base added per
addition and measurements were taken every 0.2–0.3 pH units.
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General Procedure for Buchwald-Hartwig Cross-Coupling Reactions
A mixture of Aryl ONf (0.500 mmol), amide/carbamate/sulfonamide reagent (1.2 equiv.),
K3PO4 (213 mg, 1.00 mmol, 2.0 equiv.), G3-Pd-t-BuXPhos (4 mg, 0.005 mmol, 0.01 equiv.)
and anhydrous PhMe (1.3 mL) was degassed and then stirred at 100 °C for 16 h (unless
otherwise specified). The reaction mixture was concentrated under a stream of N2 to give a
solid which was collected using vacuum filtration and washed with H2O (ca. 250 mL).* The
crude material was suspended in Et2O (5 mL), stirred and allowed to settle for 2 min before
being drained. This step was repeated once more to give the title compound.
*
For sulfonamide derivatives, the pH of the crude material was adjusted to pH = 1 prior to
washing with H2O.
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N-(4-Methyl-2-oxo-2H-chromen-7-yl)benzamide (1). Compound 1 was prepared from 5 and
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BzNH2, according to the general procedure, to give the title compound (119 mg, 85%) as a
7
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white solid. Rf = 0.40 (50% EtOAc in pet. spirits). m.p. 250–252 °C (lit. 246–248 °C).44 1
H
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NMR (DMSO-d6, 500 MHz) δ 10.65 (s, 1H), 7.98 (d, J = 10.0 Hz, 2H), 7.95 (br s, H8, 1H),
7.77 (br s, 2H), 7.63 (d, J = 5.0 Hz, 1H), 7.56 (app. t, J = 10.0, 5.0 Hz, 2H), 6.30 (s, 1H), 2.43
(d, J = 1.2 Hz, 3H). 13C{1H} NMR (DMSO-d6, 125 MHz) δ 166.1, 160.1, 153.5, 153.2, 142.6,
134.4, 132.0, 128.5, 127.8, 125.8, 116.2, 115.3, 112.5, 106.6, 18.0. HRMS (ESI-TOF) m/z: [M
+ H]+ calcd for C17H13NO3 280.0968; found 280.0974. Anal. RP-HPLC: tR 12.37 min, purity
>99%. UV-Vis (1% DMSO in H2O): λmax (ε) = 322 nm (8,300 M-1 cm-1). Fluorescence (1%
DMSO in H2O): λex = 322 nm, λmax = 430 nm (ΦF = 0.06), Stokes shift = 7,800 cm-1. Data is
in accordance with literature.51
4-Nitrobenzyl (4-methyl-2-oxo-2H-chromen-7-yl)carbamate (3). Compound 3 was
prepared from 5 and 4-nitrobenzylcarbamate,22 according to the general procedure, to give a
brown solid. The crude material was suspended in i-PrOH (20 mL), stirred and allowed to settle
for 2 min before being drained. This step was repeated once more to give the title compound
(150 mg, 87%) as a teal green solid. m.p. 248–250 °C (lit. >250 °C).15 1H NMR (DMSO-d6,
500 MHz) δ 10.42 (s, 1H), 8.28 (d, J = 8.6 Hz, 2H), 7.72–7.70 (m, 3H), 7.55 (d, J = 1.3 Hz,
13
1H), 7.42 (dd, J = 8.7, 1.3 Hz, 1H), 6.24 (s, 1H), 5.35 (s, 2H), 2.39 (s, 3H). C{1H} NMR
(DMSO-d6, 125 MHz) δ 160.0, 153.8, 153.2, 152.9, 147.2, 144.1, 142.5, 128.6, 126.1, 123.7,
114.5, 114.3, 112.0, 104.6, 65.0, 18.0. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H14N2O6
355.0925; found 355.0934. Anal. RP-HPLC: tR 12.65 min, purity >99%. Data is in accordance
with literature.15
4-Methyl-2-oxo-2H-chromen-7-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (5). A
stirring mixture of 4-methylumbelliferone (3.018 g, 17.13 mmol), K2CO3 (3.560 g,
25.76 mmol) in MeCN (90 mL) was treated with perfluorobutanesulfonyl fluoride (3.4 mL,
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18.93 mmol) for 2 h. After this time H2O (ca. 100 mL) was added to the reaction mixture to
give a precipitate which was collected using vacuum filtration. The filter cake was washed with
H2O to give the title compound (7.510 g, 96%) as a fluffy white powder. m.p. 96–97 °C. (lit.
96 °C).52 1H NMR (DMSO-d6, 500 MHz) δ 7.96 (d, J = 8.9 Hz, 1H), 7.74 (d, J = 2.5 Hz, 1H),
7.53 (dd, J = 8.9, 2.5 Hz, 1H), 6.52 (d, J = 1.2 Hz, 1H), 2.46 (d, J = 1.2 Hz, 3H). 13C{1H} NMR
(DMSO-d6, 125 MHz) δ 159.1, 153.5, 152.4, 150.5, 127.7, 120.2, 117.4, 115.3, 110.3, 18.2. 19F
NMR (DMSO-d6, 470 MHz) δ −80.09 (t, J = 10.1 Hz, 3F), −108.83 (t, J = 14.1 Hz, 2F),
−120.74–−120.79 (m, 2F), −125.42–−125.49 (m, 2F). HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C14H7F9O5S 458.9943; found 458.9948. Anal. RP-HPLC: tR 14.64 min, purity >99%.
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4-Fluoro-N-(4-Methyl-2-oxo-2H-chromen-7-yl)benzamide (6). Compound 6 was prepared
from 5 and 4-fluorobenzamide, according to the general procedure, to give the title compound
(136 mg, 91%) as a white solid. m.p. 286–288 °C. 1H NMR (DMSO-d6, 500 MHz) δ 10.65 (s,
1H), 8.05–8.01 (m, 2H), 7.93 (s, 1H), 7.78–7.74 (m, 2H), 7.42–7.39 (m, 2H), 6.30 (s, 1H), 2.42
(d, J = 1.2 Hz, 3H). 13C{1H} NMR (DMSO-d6, 125 MHz) δ 165.0, 164.3 (d, 1JC–F = 248.2 Hz),
160.1, 153.5, 153.1, 142.5, 130.9 (d, 4JC–F = 2.9 Hz), 130.6 (d, 3JC–F = 9.1 Hz), 125.8, 116.2,
2
115.5 (d, JC–F = 21.8 Hz), 115.4, 112.5, 106.6, 18.0. 19F NMR (470 MHz, DMSO-d6) δ
−108.04 (s, 1F). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H12FNO3 298.0874; found
298.0877. Anal. RP-HPLC: tR 12.48 min, purity >99%.
4-Trifluoromethyl-N-(4-methyl-2-oxo-2H-chromen-7-yl)benzamide (7). Compound 7 was
prepared from 5 and 4-(trifluoromethyl)benzamide, according to the general procedure, to give
the title compound (104 mg, 59%) as a white static solid. Compound 7 was also prepared using
G3-Pd-t-BuBrettPhos (5 mg, 0.005 mmol, 0.01 equiv.) to give the title compound (117 mg,
1
68%) as a white static solid. m.p. >300 °C. H NMR (DMSO-d6, 500 MHz) δ 10.85 (s, 1H),
8.18 (d, J = 7.7 Hz, 2H), 7.95–7.94 (m, 3H), 7.80–7.75 (m, 2H), 6.31 (s, 1H), 2.43 (d, J = 1.2
Hz, 3H). 13C{1H} NMR (DMSO-d6, 125 MHz) δ 165.0, 160.0, 153.5, 153.1, 142.2, 138.3, 131.7
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(q, 2JC-F = 31.9 Hz), 128.8, 125.9, 125.5 (q, 3JC-F = 3.6 Hz), 123.9 (q, 1JC-F = 270.9 Hz), 116.2,
115.6, 112.7, 106.8, 18.0. 19F NMR (470 MHz, DMSO-d6) δ −61.36 (s, 3F). HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C18H12F3NO3 348.0842; found 348.0834. Anal. RP-HPLC: tR 13.08
min, purity >99%.
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4-Nitro-N-(4-methyl-2-oxo-2H-chromen-7-yl)benzamide (8). Compound 8 was prepared
from 5 and 4-nitrobenzamide, according to the general procedure, to give a brown solid. The
crude material was dissolved in DMSO (5 mL), the addition of H2O (30 mL) gave a precipitate
that was collected using vacuum filtration to give the title compound (50 mg, 31%) as a yellow
solid. Compound 8 was also prepared using G3-Pd-t-BuBrettPhos (5 mg, 0.005 mmol, 0.01
equiv.) and following the same work-up to give the title compound (54 mg, 34%) as a yellow
solid. m.p. >300 °C. 1H NMR (DMSO-d6, 500 MHz) δ 10.95 (s, 1H), 8.40 (d, J = 7.8 Hz, 2H),
8.21 (d, J = 7.9 Hz, 2H), 7.94 (s, 1H), 7.81 (d, J = 8.6 Hz, 1H), 7.76 (d, J = 8.6 Hz, 2H), 6.32
(s, 1H), 2.43 (s, 3H). 13C{1H} NMR (DMSO-d6, 125 MHz) δ 164.5, 160.0, 153.5, 153.1, 149.4,
142.1, 140.0, 129.4, 126.0, 123.7, 116.3, 115.8, 112.8, 106.9, 18.0. HRMS (ESI-TOF) m/z: [M
+ H]+ calcd for C17H12N2O5 325.0819; found 325.0815. Anal. RP-HPLC: tR 12.37 min, purity
>98%. Data is in accordance with literature.53
4-Methoxy-N-(4-methyl-2-oxo-2H-chromen-7-yl)benzamide (9). Compound 9 was
prepared from 5 and 4-methoxybenzamide, according to the general procedure (reaction time
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was 48 h) to give the title compound (143 mg, 92%) as a white solid. m.p. 233–235 °C. H
NMR (500 MHz, DMSO-d6) δ 10.47 (s, 1H), 7.99 (d, J = 8.7 Hz, 2H), 7.94 (s, 1H), 7.75 (s,
2H), 7.09 (d, J = 8.7 Hz, 2H), 6.27 (s, 1H), 3.85 (s, 3H), 2.41 (s, 3H). 13C{1H} NMR (125 MHz,
DMSO-d6) δ 165.4, 162.3, 160.1, 153.6, 153.2, 142.8, 129.8, 126.4, 125.7, 116.1, 115.1, 113.7,
112.3, 106.5, 55.5, 18.0. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H15NO4 310.1074;
found 310.1074. Anal. RP-HPLC: tR 12.39 min, purity >97%. Data is in accordance with
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2-Fluoro-N-(4-methyl-2-oxo-2H-chromen-7-yl)benzamide (10). Compound 10 was
prepared from 5 and 2-fluorobenzamide, according to the general procedure (reaction time was
48 h) to give the title compound (100 mg, 66%) as a brown solid. m.p. 195–198 °C. 1H NMR
(500 MHz, DMSO-d6) δ 10.85 (s, 1H), 7.86 (d, J = 1.3 Hz, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.71
(app. t, J = 7.3 Hz, 1H), 7.65 (dd, J = 8.7, 1.3 Hz, 1H), 7.63–7.60 (m, 1H), 7.40–7.35 (m, 2H),
6.30 (s, 1H), 2.42 (s, 3H). 13C{1H} NMR (125 MHz, DMSO-d6) δ 163.3, 160.0, 158.9 (d, 1JC–
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F = 249.1 Hz), 153.6, 153.1, 142.1, 133.0 (d, JC–F = 8.4 Hz), 130.0 (d, JC–F = 2.3 Hz) 126.0,
124.7 (d, 3JC–F = 3.6 Hz), 124.5 (d, 2JC–F = 14.5 Hz), 116.3 (d, 2JC–F = 21.6 Hz), 115.7, 115.5,
112.6, 106.2, 18.0. 19F NMR (470 MHz, DMSO-d6) δ −114.46 (s, 1F). HRMS (ESI-TOF) m/z:
[M + H]+ calcd for C17H12FNO3 298.0874; found 298.0878. Anal. RP-HPLC: tR 12.21 min,
purity >99%.
N-(4-Methyl-2-oxo-2H-chromen-7-yl)-2-methylbenzamide (11). Compound 11 was
prepared from 5 and 2-methylbenzamide, according to the general procedure, to give the title
compound (128 mg, 88%) as an off-white solid. m.p. 227–229 °C. (lit. 226–228 °C).51 1H NMR
(DMSO-d6, 500 MHz) δ 10.73 (s, 1H), 7.88 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 8.4
Hz, 1H), 7.51 (d, J = 7.3 Hz, 1H), 7.42 (app. t, J = 7.3 Hz, 1H), 7.34–7.30 (m, 2H), 6.29 (s,
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1H), 2.42 (s, 3H), 2.40 (s, 3H). C{1H} NMR (DMSO-d6, 125 MHz) δ 168.4, 160.0, 153.6,
153.1, 142.6, 136.6, 135.4, 130.7, 130.1, 127.3, 125.9, 125.7, 115.6, 115.3, 112.4, 106.1, 19.3,
18.0. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H15NO3 294.1125; found 294.1122. Anal.
RP-HPLC: tR 12.33 min, purity >99%. UV-Vis (1% DMSO in H2O): λmax (ε) = 328 nm (11,000
M-1 cm-1). Fluorescence (1% DMSO in H2O): λex = 328 nm, λmax = 420 nm (ΦF = 0.06), Stokes
shift = 6,678 cm-1. Data is in accordance with literature.51
2-Methoxy-N-(4-methyl-2-oxo-2H-chromen-7-yl)benzamide (12). Compound 12 was
prepared from 5 and 2-methoxybenzamide, according to the general procedure, to give the title
compound (141 mg, 92%) as a light brown solid. m.p. 217–219 °C. 1H NMR (DMSO-d6, 500
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MHz) δ 10.52 (s, 1H), 7.90 (s, 1H), 7.74 (d, J = 8.7 Hz, 1H), 7.67 (d, J = 8.7 Hz, 1H), 7.63 (dd,
J = 7.5, 1.3 Hz, 1H), 7.53 (app. t, J = 8.5 Hz, 1H), 7.20 (d, J = 8.5 Hz, 1H), 7.09 (app. t, J =
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7.5 Hz, 1H), 6.28 (s, 1H), 3.90 (s, 3H), 2.42 (s, 3H). C{1H} NMR (DMSO-d6, 125 MHz) δ
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165.3, 160.1, 156.5, 153.7, 153.1, 142.4, 132.4, 129.6, 125.9, 124.7, 120.5, 115.7, 115.2, 112.4,
112.0, 106.1, 55.9, 18.0. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H15NO4 310.1074;
found 310.1078. Anal. RP-HPLC: tR 12.89 min, purity >98%. UV-Vis (1% DMSO in H2O):
λmax (ε) = 326 nm (3,300 M-1 cm-1). Fluorescence (1% DMSO in H2O): λex = 326 nm, λmax
443 nm (ΦF = 0.09), Stokes shift = 8,101 cm-1.
=
3-Fluoro-N-(4-methyl-2-oxo-2H-chromen-7-yl)benzamide (13). Compound 13 was
prepared from 5 and 3-fluorobenzamide, according to the general procedure, to give the title
compound (138 mg, 92%) as an off-white static solid. m.p. 282–284 °C. 1H NMR (DMSO-d6,
500 MHz) δ 10.69 (s, 1H), 7.93 (s, 1H), 7.84–7.74 (m, 3H), 7.64–7.60 (m, 1H), 7.51–7.47 (m,
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1H), 6.30 (s, 1H), 2.42 (s, 3H). C{1H} NMR (DMSO-d6, 125 MHz) δ 164.7 (d, JC–F = 2.7
Hz), 161.9 (d, 1JC–F = 243.0 Hz), 160.0, 153.5, 153.1, 142.3, 136.7 (d, 3JC–F = 7.0 Hz), 130.7
(d, 3JC–F = 8.0 Hz), 125.9, 124.1 (d, 4JC–F = 2.8 Hz), 118.9 (d, 2JC–F = 20.9 Hz), 116.2, 115.5,
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114.7 (d, JC–F = 22.8 Hz), 112.6, 106.8, 18.0. F NMR (470 MHz, DMSO-d6) δ −112.5 (s,
2F). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H12FNO3 298.0874; found 298.0872. Anal.
RP-HPLC: tR 17.53 min, purity >99%.
3-Methoxy-N-(4-methyl-2-oxo-2H-chromen-7-yl)benzamide (14). Compound 14 was
prepared from 5 and 3-methoxybenzamide, according to the general procedure, to give a beige
solid. The crude material was purified using column chromatography (EtOAc) to give the title
compound (119 mg, 79%) as a fine white solid. Rf = 0.30 (EtOAc). m.p. 195–197 °C. 1H NMR
(DMSO-d6, 500 MHz) δ 10.60 (s, 1H), 7.94 (s, 1H), 7.78–7.74 (m, 2H), 7.56 (d, J = 7.7 Hz,
1H), 7.50–7.46 (m, 2H), 7.20 (dd, J = 8.2, 1.7 Hz, 1H), 6.29 (s, 1H), 3.85 (s, 3H), 2.42 (s, 3H).
13C{1H} NMR (DMSO-d6, 125 MHz) δ 165.8, 160.0, 159.2, 153.5, 153.1, 142.5, 135.8, 129.7,
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125.8, 120.0, 117.7, 116.2, 115.4, 113.1, 112.5, 106.7, 55.4, 18.0. HRMS (ESI-TOF) m/z: [M
+ H]+ calcd for C18H15NO4 310.1074; found 310.1071. Anal. RP-HPLC: tR 12.32 min, purity
>99%.
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3,5-Dimethoxy-N-(4-methyl-2-oxo-2H-chromen-7-yl)benzamide (15). Compound 15 was
prepared from 5 and 3,5-dimethoxybenzamide, according to the general procedure to give a
brown solid. The crude material was dissolved in DMSO (3 mL) and H2O (3 mL) was added
to cause immediate precipitation. The mixture was cooled on ice and the title compound was
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collected using vacuum filtration as a beige solid (72 mg, 43%). m.p. 247–249 °C. H NMR
(500 MHz, DMSO-d6) δ 10.55 (1H, s), 7.93 (1H, s), 7.78–7.74 (2H, m), 7.12 (2H, s), 6.75 (1H,
s), 6.30 (1H, s), 3.83 (6H, s), 2.42 (3H, s).13C{1H} NMR (125 MHz, DMSO-d6) δ 165.6, 160.4,
160.1, 153.5, 153.2, 142.4, 136.4, 125.8, 116.3, 115.4, 112.5, 106.7, 105.8, 103.7, 55.6, 18.0.
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H17NO5 340.1179; found 340.1180. Anal. RP-
HPLC: tR 12.87 min, purity >99%.
N-(4-Methyl-2-oxo-2H-chromen-7-yl)-3,5-dinitrobenzamide (16). Compound 16 was
prepared from 5 and 3,5-dinitrobenzamide, according to the general procedure (0.02 equiv. of
catalyst was required) to give a brown solid. The crude material was washed with EtOH
(120 mL) to give the title compound (60 mg, 32%) as an amorphous grey solid. m.p. >300 °C.
1H NMR (500 MHz, DMSO-d6) δ 11.15 (s, 1H), 9.17 (s, 2H), 9.01 (s, 1H), 7.91 (s, 1H), 7.80
(d, J = 7.8 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 6.32 (s, 1H), 2.43 (s, 3H). 13C{1H} NMR
(125 MHz, DMSO-d6) δ 161.8, 159.9, 153.4, 153.0, 148.1, 141.6, 136.9, 128.2, 125.9, 121.4,
116.4, 116.0, 113.0, 107.2, 18.0. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H11N3O7
370.0670; found 370.0674. RP-HPLC was not performed on this compound as its solubility
was restricted to DMSO and halogenated solvents.
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N-(4-Methyl-2-oxo-2H-chromen-7-yl)isonicotinylamide (17). Compound 17 was prepared
from 5 and isonicotinamide, according to the general procedure, to give the title compound
(140 mg, 99%) as an off-white solid. m.p. >300 °C. 1H NMR (DMSO-d6, 500 MHz) δ 10.88
(s, 1H), 8.81 (d, J = 5.5 Hz, 2H), 7.93 (s, 1H), 7.89 (d, J = 5.5 Hz, 2H), 7.80 (d, J = 8.7 Hz,
1H), 7.74 (d, J = 8.7 Hz, 1H), 6.31 (s, 1H), 2.42 (s, 3H). 13C{1H} NMR (DMSO-d6, 125 MHz)
δ 164.7, 160.0, 153.5, 153.1, 150.3, 142.4, 141.7, 125.9, 121.7, 116.4, 115.7, 112.6, 106.9,
18.0. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C16H12N2O3 281.0921; found 281.0924. Anal.
RP-HPLC: tR 11.26 min, purity >97%. UV-Vis (1% DMSO in H2O): λmax (ε) = 327 nm (7,900
M-1 cm-1). Fluorescence (1% DMSO in H2O): λex = 327 nm, λmax = 445 nm (ΦF = 0.03), Stokes
shift = 8,109 cm-1. Data is in accordance with literature.16
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N-(4-Methyl-2-oxo-2H-chromen-7-yl)nicotinylamide (18). Compound 18 was prepared
from 5 and nicotinamide, according to the general procedure, to give a brown solid. The crude
material dissolved in hot DMSO (4 mL) and the title compound was isolated by adding H2O
(30 mL) and collecting the resulting white solid using vacuum filtration (128 mg, 93%). m.p.
270–272 °C. 1H NMR (DMSO-d6, 500 MHz) δ 10.82 (s, 1H), 9.13 (s, 1H), 8.79 (d, J = 3.9 Hz,
1H), 8.32 (d, J = 7.9 Hz, 1H), 7.92 (s, 1H), 7.78 (d, J = 8.7 Hz, 1H), 7.74 (d, J = 8.7 Hz, 1H),
7.61–7.57 (m, 1H), 6.30 (s, 1H), 2.42 (s, 3H). 13C{1H} NMR (DMSO-d6, 125 MHz) δ 164.7,
160.0, 153.5, 153.1, 152.5, 148.8, 142.2, 135.7, 130.2, 125.9, 123.6, 116.2, 115.6, 112.7, 106.7,
18.0. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C16H12N2O3 281.0921; found 281.0917. Anal.
RP-HPLC: tR 11.34 min, purity >99%. UV-Vis (1% DMSO in H2O): λmax (ε) = 327 nm (5,500
M-1 cm-1). Fluorescence (1% DMSO in H2O): λex = 327 nm, λmax = 432 nm (ΦF <0.01), Stokes
shift = 7,433 cm-1. Data is in accordance with literature.53
N-(4-Methyl-2-oxo-2H-chromen-7-yl)picolinylamide (19). Compound 19 was prepared
from 5 and picolinamide, according to the general procedure, to give the title compound (17
mg, 12%) as a staticky white solid. m.p. 223–225 °C. 1H NMR (DMSO-d6, 500 MHz) δ 11.09
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(s, 1H), 8.78–8.77 (m, 1H), 8.20–8.19 (m, 1H), 8.19–8.09 (m, 2H), 7.97 (d, J = 8.3 Hz, 1H),
7.78 (d, J = 8.3 Hz, 1H), 7.73–7.71 (m, 1H), 6.31 (s, 1H), 2.43 (s, 3H). 13C{1H} NMR (DMSO-
d6, 125 MHz) δ 163.2, 160.1, 153.5, 153.2, 149.4, 148.5, 141.8, 138.3, 127.3, 125.8, 122.7,
116.4, 115.6, 112.6, 106.8, 18.0. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C16H12N2O3
281.0921; found 281.0921. Anal. RP-HPLC: tR 12.33 min, purity >96%. UV-Vis (1% DMSO
in H2O): λmax (ε) = 328 nm (3,900 M-1 cm-1). Fluorescence (1% DMSO in H2O): λex = 328 nm,
λmax = 396 nm (ΦF = <0.01), Stokes shift = 4,959 cm-1. Data is in accordance with literature.16
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N-(7-amino-4-methyl-2-oxo-2H-chromen-7-yl)methylacrylamide (20). Compound 20 was
prepared from 5 (1.015 g, 2.21 mmol) and methacrylamide, according to the general procedure,
to give the title compound (483 mg, 90%) as a grey solid. m.p. 217–219 °C. 1H NMR (DMSO-
d6, 500 MHz) δ 10.19 (s, 1H), 7.84 (s, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H),
6.27 (s, 1H), 5.87 (s, 1H), 5.61 (s, 1H), 2.40 (d, J = 1.2 Hz, 3H), 1.96 (s, 1H). 13C{1H} NMR
(DMSO-d6, 125 MHz) δ 167.3, 160.1, 153.5, 153.1, 142.5, 140.0, 125.7, 120.9, 115.9, 115.1,
112.4, 106.4, 18.6, 18.0. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C14H13NO3 244.0968;
found 244.0962. Anal. RP-HPLC: tR 11.56 min, purity >99%. UV-Vis (1% DMSO in H2O):
λmax (ε) = 328 nm (8,500 M-1 cm-1). Fluorescence (1% DMSO in H2O): λex = 328 nm, λmax
402 nm (ΦF <0.01), Stokes shift = 5,612 cm-1. Data is in accordance with literature.54
=
N-(4-Methyl-2-oxo-2H-chromen-7-yl)propanamide (21). Compound 21 was prepared from
5 and propanamide, according to the general procedure. The reaction mixture was concentrated
and then acidified using sat. KH2PO4 (20 mL), before the solid was collected using vacuum
filtration and washed according to the general procedure, to give the title compound (95 mg,
83%) as a fluffy white solid. Compound 21 was also prepared using G3-Pd-t-BuBrettPhos (5
mg, 0.005 mmol, 0.01 equiv.) to give the title compound (92 mg, 81%) as a fluffy white solid.
m.p. 235–237 °C. 1H NMR (DMSO-d6, 500 MHz) δ 10.37 (s, 1H), 7.77 (s, 1H), 7.70 (d, J =
8.4 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 6.25 (s, 1H), 2.39–2.36 (m, 5H) 1.09 (t, J = 7.2 Hz, 3H).
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13C{1H} NMR (DMSO-d6, 125 MHz) δ 172.7, 160.1, 153.7, 153.2, 142.7, 125.9, 115.0, 114.7,
112.1, 105.3, 29.6, 18.0, 9.4. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C13H13NO3 232.0968;
found 232.0973. Anal. RP-HPLC: tR 11.28 min, purity >99%. UV-Vis (1% DMSO in H2O):
λmax (ε) = 325 nm (15,000 M-1 cm-1). Fluorescence (1% DMSO in H2O): λex = 325 nm, λmax
398 nm (ΦF = 0.71), Stokes shift = 5,644 cm-1. Data is in accordance with literature.53
=
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N-(4-Methyl-2-oxo-2H-chromen-7-yl)butanamide (22). Compound 22 was prepared from 5
and butanamide, according to the general procedure. The reaction mixture was concentrated
and then acidified using sat. KH2PO4 (20 mL), before the solid was collected using vacuum
filtration and washed according to the general procedure, to give the title compound (65 mg,
54%) as a fine white solid. m.p. 209–211 °C. 1H NMR (DMSO-d6, 500 MHz) δ 10.31 (s, 1H),
7.77 (d, J = 1.8 Hz, 2H), 7.70 (d, J = 8.7 Hz, 1H), 7.48 (dd, J = 8.7, 1.8 Hz, 1H), 6.25 (s, 1H),
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2.39 (s, 3H), 2.34 (t, J = 8.3 Hz, 2H), 1.66–1.60 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H). C{1H}
NMR (DMSO-d6, 125 MHz) δ 172.0, 160.1, 153.7, 153.2, 142.6, 125.9, 115.0, 114.8, 112.1,
105.4, 38.4, 18.4, 18.0, 13.6. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C14H15NO3 246.1125;
found 246.1132. Anal. RP-HPLC: tR 11.81 min, purity >99%. UV-Vis (1% DMSO in H2O):
λmax (ε) = 325 nm (4,800 M-1 cm-1). Fluorescence (1% DMSO in H2O): λex = 325 nm, λmax
399 nm (ΦF = 0.68), Stokes shift = 5,707 cm-1.
=
N-(4-methyl-2-oxo-2H-chromen-7-yl)adamantane-1-carboxamide (23). Compound 23 was
prepared from 5 and adamantane-1-carboxamide, according to the general procedure. The
reaction mixture was concentrated and then acidified using sat. KH2PO4 (20 mL), before the
solid was collected using vacuum filtration and washed with H2O (100 mL) and MeOH (2 ×
5 mL), to give the title compound (41 mg, 25%) as white solid. 1H NMR (500 MHz, DMSO-
d6) δ 9.51 (s, 1H), 7.85 (s, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.65 (d, J = 8.6 Hz, 1H), 6.25 (s, 1H),
2.40 (s, 3H), 2.03 (app. s, 3H), 1.92 (app. s, 6H), 1.71 (app. s, 6H). 13C{1H} NMR (125 MHz,
DMSO-d6) δ 176.7, 160.1, 153.5, 153.2, 142.9, 125.6, 115.9, 114.9, 112.2, 106.3, 41.3, 38.1,
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35.9, 27.6, 18.0. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C21H23NO3 338.1751; found
338.1751. RP-HPLC was not performed on this compound as its solubility was restricted to
DMSO and halogenated solvents.
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Ethyl 2-((4-methyl-2-oxo-2H-chromen-7-yl)amino)-2-oxoacetate (24). Compound 24 was
prepared from 5 and ethyl oxamate, according to the general procedure (0.02 equiv. of catalyst
was required and reaction time was 48 h) to give the title compound (132 mg, 94%) as a beige
solid. m.p. 213–215 °C. 1H NMR (DMSO-d6, 500 MHz) δ 11.18 (s, 1H), 7.85 (s, 1H), 7.78–
7.75 (m, 2H), 6.32 (s, 1H), 4.32 (q, J = 7.1 Hz, 2H), 2.41 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H).
13C{1H} NMR (DMSO-d6, 125 MHz) δ 160.2, 159.9, 155.8, 153.3, 153.0, 140.9, 126.0, 116.4,
116.2, 113.0, 107.2, 62.6, 18.0, 13.8. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C14H13NO5
276.0866; found 276.0870. Anal. RP-HPLC: tR 11.36 min, purity >99%.
7-(tert-Butoxycarbonylamino)-4-methyl coumarin (25). Compound 25 was prepared from 5
and t-butyl carbamate,according to the general procedure (0.02 equiv. of catalyst was required)
to give a brown solid. The crude material was purified using column chromatography (50%
CH2Cl2 in pet. spirits–10% EtOAc in CH2Cl2) to give the title compound (76 mg, 55%) as a
yellow powder. Rf = 0.62 (10% EtOAc in CH2Cl2). m.p. 144–146 °C. 1H NMR (DMSO-d6, 500
MHz) δ 9.87 (s, 1H), 7.66 (d, J = 8.7 Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H), 7.41 (dd, J = 8.7, 2.0
Hz, 1H), 6.22 (s, 1H), 2.38 (s, 3H), 1.49 (s, 9H). 13C{1H} NMR (DMSO-d6, 125 MHz) δ 160.1,
153.8, 153.2, 152.5, 143.2, 125.9, 114.2, 114.1, 111.7, 104.2, 80.0, 28.0, 18.0. HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C15H17NO4 276.1230; found 276.1223. Anal. RP-HPLC: tR 12.85
min, purity >94%. UV-Vis (1% DMSO in H2O): λmax (ε) = 327 nm (15,600 M-1 cm-1).
Fluorescence (1% DMSO in H2O): λex = 327 nm, λmax = 403 nm (ΦF = 0.94), Stokes shift =
5,767 cm-1. UV-Vis (DMSO): λmax (ε) = 330 nm (18,000 M-1 cm-1). Fluorescence (DMSO): λex
= 330 nm, λmax = 389 nm (ΦF = 0.49), Stokes shift = 4,596 cm-1. UV-Vis (CHCl3): λmax (ε) =
329 nm (15,600 M-1 cm-1). Fluorescence (CHCl3): λex = 329 nm, λmax = 389 nm (ΦF = 0.32),
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Stokes shift = 4,688 cm-1. UV-Vis (PhMe): λmax (ε) = 327 nm (15,400 M-1 cm-1). Fluorescence
(PhMe): λex = 327 nm, λmax = 382 nm (ΦF = 0.04), Stokes shift = 4,403 cm-1. Data is in
accordance with literature.55
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Benzyl (4-methyl-2-oxo-2H-chromen-7-yl)carbamate (26). Compound 26 was prepared
from 5 and benzyl carbamate, according to the general procedure, to give the title compound
(115 mg, 71%) as a grey solid. m.p. 208–210 °C (lit. 228–230 °C).56 1H NMR (500 MHz,
DMSO-d6) δ 10.28 (s, 1H), 7.69 (d, J = 8.7 Hz, 1H), 7.55 (s, 1H), 7.45 (app. d, J = 7.1 Hz, 2H),
7.41 (app. t, J = 7.4 Hz, 3H), 7.36 (app. t, J = 6.7 Hz, 1H), 7.23 (s, 1H), 5.19 (s, 2H), 1.31 (s,
3H). 13C{1H} NMR (125 MHz, DMSO-d6) δ 160.0, 153.8, 153.2, 153.2, 142.7, 136.2, 128.5,
128.3, 128.2, 126.1, 114.4, 114.2, 111.9, 104.4, 66.3, 18.0. HRMS (ESI-TOF) m/z: [M + H]+
calcd for C18H15NO4 310.1074; found 310.1080. Anal. RP-HPLC: tR 12.87 min, purity >97%.
Data is in accordance with literature except for the recorded melting point which was measured
after recrystallisation from EtOH as per literature precedent.56
4-Chlorobenzyl (4-methyl-2-oxo-2H-chromen-7-yl)carbamate (27). Compound 27 was
prepared from 5 and 4-chlorobenzylcarbamate (42), according to the general procedure (0.02
equiv. of catalyst was required and reaction time was 48 h) to give a beige solid. The crude
material was dry loaded onto SiO2 in MeOH and purified using column chromatography (50%
EtOAc in pet. spirits) to give the title compound (77 mg, 46%) as a yellow powder. Rf = 0.48
(EtOAc in pet. spirits). m.p. 239–241 °C. 1H NMR (DMSO-d6, 500 MHz) δ 10.31 (s, 1H), 7.69
(d, J = 8.7 Hz, 1H), 7.55 (s, 1H), 7.47 (br s, 4H), 7.41 (d, J = 8.7 Hz, 1H), 6.24 (s, 1H), 5.19 (s,
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2H), 2.39 (s, 3H). C{1H} NMR (DMSO-d6, 125 MHz) δ 160.0, 153.8, 153.2, 153.1, 142.6,
135.3, 132.8, 130.1, 128.5, 126.1, 114.5, 114.3, 112.0, 104.5, 65.4, 18.0. HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C18H1435ClNO4 344.0684; found 344.0681. Anal. RP-HPLC: tR 13.22
min, purity >91%.
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