N-Substituted 7-aminocoumarins can be synthesized from readily available 7-hydroxycoumarins via alkylation with α-bromoacetamides and subsequent tandem O → N Smiles rearrangement-amide hydrolysis. The key rearrangement sequence proceeds under mild conditions to provide convenient access to various N-alkyl and N-aryl products in moderate to high yields. The process is operationally simple, inexpensive, transition-metal-free, and can be telescoped into a one-pot process.
N-Substituted 7-aminocoumarins can be synthesized from readily available 7-hydroxycoumarins via alkylation with α-bromoacetamides and subsequent tandem O → N Smiles rearrangement-amide hydrolysis. The key rearrangement sequence proceeds under mild conditions to provide convenient access to various N-alkyl and N-aryl products in moderate to high yields. The process is operationally simple, inexpensive, transition-metal-free, and can be telescoped into a one-pot process.
The coumarin structural motif continues
to attract significant
attention owing to its presence in natural product scaffolds,[1] interesting biological activities,[2−4] and useful photophysical properties.[5] In addition to xanthene- and BODIPY-based dyes, coumarins also represent
one of the major classes of small molecules amenable to developing
fluorescence-based imaging tools for biological and analytical applications.[6] Consequently, modification of these molecules
has been heavily investigated, resulting in a large array of valuable
luminescent probes and chemical tools.[5] Coumarins bearing nitrogen substitution at the 7-position are highly
desirable due to their red-shifted spectral properties, wider pH working
range, photostability, and synthetic tunability as compared to their
hydroxy analogues.[7] Accordingly, 7-aminocoumarins
are commonly employed as central scaffolds in fluorescence applications.[5,8] Construction of these molecules has been historically achieved via
Pechmann and related condensation reactions using a suitable aminophenol
(Figure ).[9] While synthetically simple, the requisite harsh
conditions and limited substrate availability preclude access to structural
diversity. More recently, metal-catalyzed aminations of sulfonates
have expanded access to aminocoumarins.[10,11] However, alternative
methods that are operationally simple, transition-metal-free, avoid
sensitive intermediates, and provide improved chemoselectivity remain
highly desirable. We envisioned that a simple amination of inexpensive
and readily available 7-hydroxycoumarins would present an attractive
route.
Figure 1
Methods for synthesizing 7-aminocoumarins: (a) Pechmann condensation
of aminophenols, (b) Buchwald–Hartwig cross-coupling of sulfonylated
hydroxycoumarins, and (c) amination of coumarin ethers via Smiles
rearrangement–hydrolysis.
Methods for synthesizing 7-aminocoumarins: (a) Pechmann condensation
of aminophenols, (b) Buchwald–Hartwig cross-coupling of sulfonylated
hydroxycoumarins, and (c) amination of coumarin ethers via Smiles
rearrangement–hydrolysis.The Smiles rearrangement presents a classical and
underutilized
route for incorporating nitrogen functionality into aromatic systems.[12−14] Bayles and co-workers first detailed the rearrangement of 2-aryloxypropanamides
into corresponding anilide products when treated with sodium hydride
and heated in DMF or hexamethylphosphoramide.[15,16] Subsequent investigations have expanded this amide-based reactivity
for the conversion of phenols into primary or secondary anilides or
anilines upon hydrolysis but remain limited by harsh conditions and
high temperatures.[17−21] Owing to its electron-withdrawing lactone, we postulated that coumarins
may prove amenable to a milder process that might avoid the competitive
reactivity of conjugate addition at the 4-position or lactone opening.[5,22,23] We were encouraged by a recent
report of a tandem substitution–Smiles rearrangement of aminophenols
on 4-bromocoumarins at relatively low temperatures.[24] We therefore sought to determine whether 7-hydroxycoumarins
may be efficiently converted to a diverse array of 7-aminocoumarins
via an amide-based rearrangement–hydrolysis strategy.
Results and Discussion
To investigate the viability
of the proposed rearrangement, several
N-substituted acetamide-linked coumarins were prepared as shown in Scheme . Acylation of amines
with bromoacetyl bromide yielded α-bromoacetamides, and subsequent
alkylation with 7-hydroxy-4-methylcoumarin (3a) provided
a simple, efficient, and chromatography-free route to analytically
pure substrates. Previous studies have established significant Thorpe–Ingold
effects with respect to linker substitution in Smiles rearrangements.[13,15] Exhaustive efforts to generate the gem-dimethylated substrate via
alkylation with 2-methyl-2-bromopropionamide proved unsuccessful.
Scheme 1
Synthesis of Acetamide-Linked Coumarin Substrates
Initial attempts to induce rearrangement of
primary or N-alkyl acetamide substrates yielded decomposition
and complex
mixtures under a range of basic conditions. However, treatment of N-aryl substrates with potassium tert-butoxide
and mild heat interestingly yielded rearranged and hydrolyzed products
as indicated by analysis of the crude reaction. Efforts to optimize
this tandem process using 1H NMR analysis were complicated
by overlapping signals of intermediates, byproducts, and common internal
standards. Instead, 19F NMR was utilized as a convenient
method for identifying optimal conditions for the tandem rearrangement–hydrolysis
process using ortho-fluorinated compound 4aa as a model
substrate (Table ).
Table 1
Optimization of the Rearrangement–Hydrolysis
Reactiona
entrya
solvent
base
modification
% yieldb
% conversionb
1
THF
KOt-Bu
8
20
2
MeCN
KOt-Bu
19
23
3
DMA
KOt-Bu
68
89
4
DMSO
KOt-Bu
50
55
5
DMF
KOt-Bu
75
87
6
DMF
K2CO3
49
50
7
DMF
Cs2CO3
75
85
8
DMF
K3PO4
56
62
9
DMF
KOH
72
76
10
DMF
NaH
69
82
11
DMF
Cs2CO3
3 Å mol sieves
38
42
12
DMF
Cs2CO3
H2O (1 equiv)
26
30
13
DMF
Cs2CO3
2 equiv base
73
79
14
DMF
Cs2CO3
70 °C
84
96
15
DMF
KOt-Bu
70 °C
78
88
Reactions were performed on a 40
mg scale.
Determined via analysis of the crude reaction via 19F NMR (in DMSO-d6) using 4,4′-difluorobiphenyl
as an internal standard.
Reactions were performed on a 40
mg scale.Determined via analysis of the crude reaction via 19F NMR (in DMSO-d6) using 4,4′-difluorobiphenyl
as an internal standard.A survey of various polar aprotic solvents indicated
DMF as the
optimal solvent. The notably limited solubility of the amide substrates
is a key factor in the poor yields and conversions when using less
polar solvents (e.g., THF, MeCN). Bases with a range of strengths
were effective at inducing the rearrangement and hydrolysis, although
stronger bases tended to form more complex mixtures and decomposition.
Smiles rearrangements employing amide nucleophiles typically employ
several equivalents of bases with conjugate acid pKa values ≥ 16, most commonly NaH or hydroxide.
Carbonate bases surprisingly proved suitable for the present transformation,
with cesium carbonate providing similar yields as stronger bases and
with cleaner reaction profiles. Compatibility with this milder base
notably avoids potential safety concerns when heating in DMF or DMSO.[25,26] Addition of 3 Å molecular sieves inhibited the reaction, consistent
with involvement of adventitious water in the amide hydrolysis. Additional
water or base yielded similar deleterious results.[27] Performing the reaction with Cs2CO3 at 70 °C improved conversion without significant decomposition.Having identified optimized conditions, the scope of the rearrangement–hydrolysis
reaction was next explored (Scheme ). With respect to the amide component, substrates
comprising neutral or electron-rich anilines underwent successful
conversion to product in good yields (5ba–5fa). Steric hindrance did not noticeably inhibit reactivity
and afforded ortho-substituted products in good to moderate yield,
including 2,6-dimethyl product 5ea. Electron-withdrawing
moieties including halogens (5ga and ha)
and esters (5ia) were tolerated, albeit with more attenuated
reactivity, increased decomposition, and more moderate yields. Nitroaniline
derivative 4ja, in addition to the limited solubility,
produced only trace amounts of product, even when the reaction was
performed at elevated temperatures in DMSO. 1-Naphthyl substrate 4ka afforded product with good efficiency. The method also
proved suitable for alkyl amides, producing N-benzyl
(5la) and N-butyl (5ma)
products in useful yields. In contrast, applying the standard reaction
conditions to a primary amide substrate yielded a more complex mixture
including only minor amounts of 7-aminocoumarin 5na and
significant amounts of rearranged yet unhydrolyzed intermediate (vida infra). A tandem in situ acidic hydrolysis of the intermediate
afforded the primary aminocoumarin in moderate yield.
Scheme 2
Substrate
Scope of Amines and 7-Hydroxycoumarins in the Tandem Rearrangement–Hydrolysis
Reaction
Reactions were performed
on a
0.31 mmol scale. Yields refer to isolated yields following column
chromatography. bReaction was performed under standard
conditions, followed by HCl, EtOH, 90 °C for 5 h. cReaction was performed at 100 °C for 30 h.
Substrate
Scope of Amines and 7-Hydroxycoumarins in the Tandem Rearrangement–Hydrolysis
Reaction
Reactions were performed
on a
0.31 mmol scale. Yields refer to isolated yields following column
chromatography. bReaction was performed under standard
conditions, followed by HCl, EtOH, 90 °C for 5 h. cReaction was performed at 100 °C for 30 h.Structural variation on the coumarin skeleton was also explored.
Coumarins with substitution at the 4-position are commonly employed
in order to attenuate known vinylogous reactivity. Umbelliferone derivative 4cb, which is unsubstituted at the 4-position, successfully
afforded product 5cb without any observed competing reactivity.
4-Methylcoumarins bearing additional substitution at the 3- or 6-position
similarly provided the desired products (5cc-5cd) in good yields. Notably, 6-chloro derivative 4cd avoided
competitive ortho SNAr reactivity of the
amide, which has been observed in related processes to afford benzoxazinone
derivatives.[17] In contrast, bromo analogue 4ce failed to react even under significantly higher temperatures,
potentially arising from limited solubility and increased steric hindrance
in proximity to the desired ipso attack. Owing to stabilization of
the key Meisenheimer intermediate, electronically deficient arenes
are generally exceptional substrates in processes invoking Smiles
rearrangements. Surprisingly, 4-trifluoromethylcoumarins bearing either N-aryl (4cf) or N-alkyl amides
(4lf) displayed attenuated reactivity, affording poorer
yields and increased decomposition under the reaction conditions.
A 3-acetyl-substituted substrate rapidly formed a complex mixture
without evidence of the desired product 5cg, potentially
due to undesired reactivity at the doubly activated and unhindered
4-position.The alkylation, rearrangement, and hydrolysis steps
occur under
reasonably similar basic conditions with heating, inviting the possibility
of a tandem procedure for providing direct conversion of the hydroxycoumarin
to the amine-functionalized product.[18] Gratifyingly,
treatment of coumarin 3a and bromoacetamide 2c with the standard rearrangement conditions and 2.4 equiv of Cs2CO3 provided the desired aminocoumarin product 5ca with only slightly lower efficiency compared to the stepwise
procedure (see the Supporting Information). Alternatively, a one-pot process in which sequential alkylation
and rearrangement–hydrolysis are controlled via temperature
and base addition improved the isolated yield to 85% (Scheme ). Application of this strategy
to other substrates produced aminocoumarins 5cd and 5la in only slightly depressed yields as compared to the one-step
procedure, indicating compatibility with variation in amine and hydroxycoumarin
precursors. This procedure presents a convenient and direct amination
of the hydroxyl unit without a separate prefunctionalization step.
Experiments were performed to provide additional
information on
the nature of the reaction sequence (Figure ). Exposure of tertiary amide 4oa to standard rearrangement conditions did not effect any reaction,
and only the starting material was indicated by NMR analysis of the
crude reaction mixture (Figure a). When monitored by 1H NMR, treatment of substrate 4da with 1.5 equiv of potassium tert-butoxide
at room temperature was accompanied by the appearance of a single
intermediate, exhibiting significant upfield shifts to hydrogens associated
with the aniline ring and methylene linker as well as loss of the
amide hydrogen signal (Figure b, also see the Supporting Information). Slow conversion of this ostensibly deprotonated intermediate to
product 5da was observed by heating at 50 °C. Interestingly,
primary amide 4na formed significant amounts of the direct
rearrangement compound 5na′ along with minor amounts
of the subsequent hydrolysis product 5na (Figure c).[28] Hydrolysis of intermediate 5na′ may be impeded
by favorable deprotonation of the amide proton affording the anion
and decreased reactivity at the amide carbonyl. Indeed, attempts to
saponify this intermediate under forcing conditions with hydroxide
proved ineffective. Such a pathway is unavailable for secondary substrates,
as the intermediate contains no acidic N–H, and their comparably
facile amide hydrolysis may also be explained by the extended conjugation
of the nitrogen into the coumarin moiety. Taken together, a mechanism
invoking a canonical base-mediated Smiles rearrangement and subsequent
amide hydrolysis (Scheme ) is consistent with the abovementioned observations and is
proposed for the present amination reaction.[16,29]
Figure 2
Mechanistic
studies: (a) treatment of tertiary amide 4oa with standard
reaction conditions, (b) stepwise analysis of the
rearrangement–hydrolysis sequence of 4da via NMR
monitoring, and (c) formation of the unhydrolyzed intermediate when
applying standard reaction conditions to primary amide 4na.
Scheme 4
Proposed Mechanism
Mechanistic
studies: (a) treatment of tertiary amide 4oa with standard
reaction conditions, (b) stepwise analysis of the
rearrangement–hydrolysis sequence of 4da via NMR
monitoring, and (c) formation of the unhydrolyzed intermediate when
applying standard reaction conditions to primary amide 4na.In summary, a method for preparing N-aryl or N-alkyl 7-aminocoumarins from readily available
hydroxylated
precursors has been developed that exploits a key O → N Smiles
rearrangement. This process is operationally simple, employs inexpensive
reagents, and avoids hydrolytically sensitive intermediates typically
required with metal-catalyzed amination methods. Notably, the alkylation–rearrangement–hydrolysis
sequence may be telescoped into a direct, one-pot amination from the
respective α-bromoacetamide. Substrates containing an array
of functionalities are tolerated, including electron-deficient anilines
and halogens, providing access to unique chemical space that may prove
challenging by existing methods. Efforts to extend this strategy to
explore new xanthene fluorophores as well as ratiometric imaging applications
are ongoing.
Experimental Section
General Information
All reactions were carried out
in flame-dried glassware under argon. Solvents were purchased as HPLC-grade
from Sigma-Aldrich and used without further purification. Umbelliferone
was purchased from Tokyo Chemical Industry Company. Cesium carbonate
was purchased from Alfa Aesar. All other reagents were purchased from
Oakwood Chemical. 1H NMR and 13C NMR data were
collected in CDCl3 (Sigma-Aldrich) or DMSO-d6 (Oakwood Chemical) at 27 °C on a 300 MHz Bruker
AVANCE III HD spectrometer. Chemical shifts (δ) are reported
in parts per million relative to residual solvent signals of CDCl3 (7.27 ppm for 1H and 77.16 ppm for 13C) or DMSO-d6 (2.50 ppm for 1H and 39.52 ppm for 13C). Splitting patterns: s, singlet;
d, doublet; t, triplet; q, quartet; m, multiplet; dd, doublet of doublets;
dq, doublet of quartets; bs, broad singlet; bd, broad doublet. Thin-layer
chromatography was performed on Baker-flex silica gel IB-F TLC plates
(J.T. Baker), and flash column chromatography was performed using
SiliaFlash P60 silica gel (SiliCycle). α-Bromoacetamides 2 are known compounds and were synthesized according to a
literature procedure.[30] Hydroxycoumarins 3c,[31]3d,[32]3e,[33] and 3g(34) were synthesized
according to literature procedures.
General Procedure 1: Synthesis of O-Alkylated
Coumarins
A round-bottom flask was charged with hydroxycoumarin
(1 equiv) and Cs2CO3 (1.2 equiv). Acetonitrile
(0.15 M) was added, followed by the respective α-bromoacetamide
(1.2 equiv), and the resulting slurry was stirred in a 50 °C
oil bath for 16 h. The solvent was removed in vacuo, and the resulting
residue was washed with CH2Cl2 or Et2O and then H2O to provide the desired O-alkylated coumarin product.
General Procedure 2: Synthesis of Aminocoumarins via Rearrangement–Hydrolysis
A solution of alkylated coumarin (0.31 mmol) in DMF (3.1 mL, 0.1
M) was prepared under argon in a dry round-bottom flask. After adding
Cs2CO3 (121 mg, 0.37 mmol), the resulting slurry
was stirred vigorously for 24 h in a 70 °C oil bath. The mixture
was cooled, the solvent was removed in vacuo, and the resulting solid
was washed with 1 M HCl (10 mL) and extracted with CH2Cl2 (3 × 10 mL). The combined organics were dried over sodium
sulfate, concentrated in vacuo, and purified via flash column chromatography
to afford the title compound.
Synthesized according to General Procedure
2 on a 0.310 mmol scale using DMSO (4.6 mL) as the solvent. TLC analysis
after heating the mixture for 24 h at 70 °C indicated significant
remaining starting material. The reaction was heated for additional
24 h at 100 °C. After cooling to rt, the reaction was poured
into 150 mL of 0.5 M HCl, and the resulting tan solid was filtered
and washed with water. Chromatographic purification using a gradient
eluent of 50:50:0–99:0:1 CH2Cl2/Hex/MeOH
provided the title compound as a white solid (48.3 mg, 38%). 1H NMR (300 MHz, DMSO-d6, ppm):
δ 8.49 (s, 1H), 7.93 (s, J = 2.3 Hz, 1H), 7.59
(d, J = 8.6 Hz, 1H), 7.56 (dd, J = 8.7, 2.3 Hz, 1H), 7.37 (d, J = 8.7 Hz, 1H), 6.91
(dd, J = 8.7, 2.3 Hz, 1H), 6.73 (d, J = 2.2 Hz, 1H), 6.10 (d, J = 1.1 Hz, 1H), 2.36 (d, J = 1.1 Hz, 3H). 13C{H} NMR (75 MHz, DMSO-d6, ppm): δ 160.3, 154.8, 153.4, 147.8,
139.0, 135.3, 131.6, 126.4, 125.4, 118.6, 115.9, 112.4, 112.0, 109.9,
101.2, 18.0. FTIR (ATR, cm–1) 3323, 2920, 1699,
1609, 1579, 1494, 1388. HRMS (EI) m/z: [M+] calcd for C16H1179Br2NO2, 406.9157; found, 406.9156.
Synthesized according to General Procedure
2. Chromatographic purification using a gradient eluent of 0%–1%
MeOH/CH2Cl2 provided the title compound as an
orange solid (62.3 mg, 67%). 1H NMR (300 MHz, DMSO-d6, ppm): δ 8.96 (s, 1H), 8.08–8.01
(m, 1H), 8.00–7.93 (m, 1H), 7.76 (d, J = 7.5
Hz, 1H), 7.60–7.45 (m, 5H), 6.92 (dd, J =
8.7, 2.2 Hz, 1H), 6.66 (d, J = 2.2 Hz, 1H), 6.03
(d, J = 1.0 Hz, 1H), 2.34 (s, 3H). Spectral data
are in agreement with literature values.[10]
7-(Benzylamino)-4-methyl-2H-chromen-2-one (5la)
Synthesized according to General Procedure 2.
Chromatographic purification using a gradient eluent of 15%–30%
EtOAc/Hex provided the title compound as a white solid (52.9 mg, 67%). 1H NMR (300 MHz, CDCl3, ppm): δ 7.41–7.28
(m, 6H), 6.56 (dd, J = 8.7, 2.4 Hz, 1H), 6.49 (d, J = 2.3 Hz, 1H), 5.99 (d, J = 1.1 Hz, 1H),
4.64 (b, 1H), 4.40 (d, J = 5.6 Hz, 2H), 2.34 (d, J = 1.1 Hz, 3H). Spectral data are in agreement with literature
values.[37]
7-(Butylamino)-4-methyl-2H-chromen-2-one (5ma)
Synthesized according to General Procedure 2.
Chromatographic purification using a gradient eluent of 10%–30%
EtOAc/Hex provided the title compound as a white solid (36.8 mg, 51%). 1H NMR (300 MHz, CDCl3, ppm): δ 7.35 (d, J = 8.6 Hz, 1H), 6.50 (dd, J = 8.6, 2.4
Hz, 1H), 6.44 (d, J = 2.3 Hz, 1H), 5.98 (d, J = 1.1 Hz, 1H), 4.19 (br s, 1H), 3.18 (q, J = 6.3 Hz, 2H), 2.35 (d, J = 1.1 Hz, 3H), 1.70–1.58
(m, 2H), 1.52–1.38 (m, 2H), 0.98 (t, J = 7.3
Hz, 3H). Spectral data are in agreement with literature values.[38]
7-Amino 4-Methyl-2H-chromen-2-one (5na)
Synthesized according to General Procedure 2. After 24
h of heating at 70 °C, the solvent was removed in vacuo, the
residue was dissolved in EtOH (3 mL), and 6 M HCl (1 mL) was added.
The resulting solution was heated to 90 °C in an oil bath for
5 h. After cooling, EtOH was removed in vacuo, the reaction was neutralized
with sat aq NaHCO3 (10 mL), and extracted with CH2Cl2 (3 × 10 mL). The combined organics were dried
over magnesium sulfate and concentrated in vacuo. Chromatographic
purification using a gradient eluent of 0%–2% MeOH/CH2Cl2 provided the title compound as a pale-yellow solid
(19.5 mg, 36%). 1H NMR (300 MHz, CDCl3, ppm):
δ 7.40 (d, J = 8.7 Hz, 1H), 6.56 (dd, J = 8.6, 2.2 Hz, 1H), 6.40 (d, J = 2.2
Hz, 1H), 6.09 (br s, 2H), 5.90 (d, J = 1.1 Hz, 1H),
2.30 (d, J = 1.1 Hz, 3H). Spectral data are in agreement
with literature values.[39]
7-(m-Tolylamino)-2H-chromen-2-one
(5cb)
Synthesized according to General Procedure
2 on a 0.226 mmol scale. Chromatographic purification using a gradient
eluent of 10:10:80 to 20:20:60 EtOAc/CH2Cl2:Hex
provided the title compound as a yellow solid (46.5 mg, 82%). 1H NMR (300 MHz, DMSO-d6, ppm):
δ 8.84 (s, 1H), 7.88 (d, J = 9.5 Hz, 1H), 7.49
(d, J = 8.7 Hz, 1H), 7.23 (t, J =
7.5 Hz, 1H), 7.04–6.98 (m, 2H), 6.94 (dd, J = 8.5, 2.2 Hz, 1H), 6.87–6.82 (m, 2H), 6.12 (d, J = 9.4 Hz, 1H), 2.30 (s, 3H). 13C{H} NMR (75 MHz, DMSO-d6, ppm): δ 160.6, 155.7, 148.2, 144.4,
140.8, 138.7, 129.4, 129.2, 123.2, 120.2, 116.9, 112.4, 110.6, 110.2,
99.7, 21.1. FTIR (ATR, cm–1) 3306, 1693, 1586, 1512,
1329. HRMS (EI) m/z: [M+] calcd for C16H13NO2, 251.0946;
found, 251.0946.
Authors: Olimpo García-Beltrán; Osvaldo Yañez; Julio Caballero; Antonio Galdámez; Natalia Mena; Marco T Nuñez; Bruce K Cassels Journal: Eur J Med Chem Date: 2014-02-11 Impact factor: 6.514
Figure 1
Scheme 1
Scheme 2
Scheme 3
Figure 2
Scheme 4